Androstane 17-beta-carboxamides as androgen receptor modulators

ABSTRACT

Compounds of structural formula as herein defined are disclosed as useful in a method for modulating the androgen receptor in a tissue selective manner in a patient in need of such modulation, as well as in a method of activating the function of the androgen receptor in a patient, and in particular the method wherein the function of the androgen receptor is blocked in the prostate of a male patient or in the uterus of a female patient and activated in bone and/or muscle tissue. These compounds are useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, female sexual dysfunction, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, prostate cancer, arthritis and joint repair, alone or in combination with other active agents.

BACKGROUND OF THE INVENTION

[0001] The androgen receptor (AR) belongs to the superfamily ofsteroid/thyroid hormone nuclear receptors, whose other members includethe estrogen receptor (ER), the progesterone receptor (PR), theglucocorticoid receptor (GR), and the mineralocorticoid receptor (MR).The AR is expressed in numerous tissues of the body and is the receptorthrough which the physiological as well as the pathophysiologicaleffects of endogenous androgen ligands, such as testosterone (T) anddihydrotestosterone (DHT), are expressed. Structurally, the AR iscomposed of three main functional domains: the ligand binding domain(LBD), the DNA-binding domain, and amino-terminal domain. A compoundthat binds to the AR and mimics the effects of an endogenous AR ligandis referred to as an AR agonist, whereas a compound that inhibits theeffects of an endogenous AR ligand is termed an AR antagonist.

[0002] Androgen ligand binding to the AR affords a ligand/receptorcomplex, which, subsequent to translocation inside the nucleus of thecell, binds to specific regulatory DNA sequences (referred to asandrogen response elements or AREs) within the promoter or enhancerregions of the target gene or genes present in the cell's nucleus. Otherproteins termed cofactors are next recruited which bind to theamino-terminal domain or the LBD of the receptor leading to genetranscription and subsequent translation to produce the protein(s)encoded by that gene or genes.

[0003] Androgen therapy has been used in the clinic to treat a varietyof male disorders, such as reproductive disorders and primary orsecondary male hypogonadism. Moreover, a number of natural or syntheticAR agonists have been clinically investigated for the treatment ofmusculoskeletal disorders, such as bone disease, hematopoieticdisorders, neuromuscular disease, rheumatological disease, wastingdisease, and for hormone replacement therapy (HRT), such as femaleandrogen deficiency. In addition, AR antagonists, such as flutamide andbicalutamide, have been used to treat prostate cancer. It wouldtherefore be useful to have available compounds that can activate(“agonize”) the function of the AR in a tissue-selective manner whichwould afford the desired beneficial osteoanabolic effects of androgensbut without the negative androgenic properties, such as virilization andinduction of an atherogenic lipid profile which can lead tocardiovascular disease.

[0004] The role of androgens in bone formation has been documented. Forexample, anabolic steroids, such as nandrolone decanoate or stanozolol,have been shown to increase bone mass in postmenopausal women. Thebeneficial effects of androgens on bone in postmenopausal osteoporosiswere documented in recent studies using combined testosterone andestrogen administration [Hofbauer, et al., “Androgen effects on bonemetabolism: recent progress and controversies,” Eur. J.

[0005] Endocrinol.140: 271-286 (1999)]. Combined treatment significantlyincreased the rate and extent of the rise in bone mineral density (BMD)in the lumbar and hip regions, relative to treatment with estrogenalone. Additionally, estrogen-progestin combinations that incorporatedan androgenic progestin (such as norethindrone), rather thanmedroxyprogesterone acetate, yielded greater improvements in hip BMD.These results have recently been confirmed in a larger 2-year,double-blind comparison study in which oral conjugated estrogen (CEE)and methyltestosterone combinations were demonstrated to be effective inpromoting accrual of bone mass in the spine and hip, while conjugatedestrogen therapy alone prevented bone loss [“A two-year, double-blindcomparison of estrogen-androgen and conjugated estrogens in surgicallymenopausal women: Effects on bone mineral density, symptoms and lipidprofiles,” J. Reprod. Med., 44: 1012-1020 (1999)]. Despite thebeneficial effects of androgens in postmenopausal women, the use ofandrogens has been limited because of the undesirable virilizing andmetabolic action of androgens. The data from Watts and colleaguesdemonstrate that hot flushes decrease in women treated with CEE andmethyltestosterone; however, 30% of these women suffered fromsignificant increases in acne and facial hair, a complication of allcurrent androgen pharmacotherapies [Watts, et al., “Comparison of oralestrogens and estrogens plus androgen on bone mineral density,menopausal symptoms, and lipid-lipoprotein profiles in surgicalmenopause,” Obstet. Gynecol., 85: 529-537 (1995)]. Moreover, theaddition of methyltestosterone to CEE markedly decreased HDL levels, asseen in other studies. Therefore, non-tissue selective AR agonists mayincrease the risk of cardiovascular disease. Thus, the virilizingpotential and negative effects on lipid profile of current androgentherapies provide a strong rationale for developing tissue-selectiveandrogen receptor agonists for bone. Reference is made to J. A. Kanis,“Other agents for generalized osteoporosis,” in Osteoporosis, BlackwellScience, Ch. 8, pp 196-227 (1994) for a discussion of non-selectiveanabolic steroids in the treatment of osteoporosis.

[0006] It is also well established that androgens play an important rolein bone metabolism in men, which parallels the role of estrogens inwomen [Anderson, et al., “Androgen supplementation in eugonadal men withosteoporosis—effects of six months of treatment on bone mineral densityand cardiovascular risk factors,” Bone, 18: 171-177 (1996)]. Even ineugonadal men with established osteoporosis, the therapeutic response totestosterone treatment provided additional evidence that androgens exertimportant osteoanabolic effects. Mean lumbar BMD increased from 0.799gm/cm² to 0.839 g/cm², in 5 to 6 months in response to 250 mg oftestosterone ester administered intramuscularly every fortnight. Acommon scenario for androgen deficiency occurs in men with stage Dprostate cancer (metastatic) who undergo androgen deprivation therapy(ADT). Endocrine orchiectomy is achieved by long acting GnRH agonists,while androgen receptor blockade is implemented with flutamide,nilutamide, bicalutamide, or RU 58841 (AR antagonists). In response tohormonal deprivation, these men suffered from hot flushes, significantbone loss, weakness, and fatigue. In a recent pilot study of men withstage D prostate cancer, osteopenia (50% vs. 38%) and osteoporosis (38%vs. 25%) were more common in men who had undergone ADT for greater thanone year than the patients who did not undergo ADT [Wei, et al.,“Androgen deprivation therapy for prostate cancer results in significantloss of bone density,” Urology, 54: 607-611 (1999)]. Lumbar spine BMDwas significantly lower in men who had undergone ADT. Thus, in additionto the use of tissue selective AR agonists for osteoporosis, tissueselective AR antagonists in the prostate that lack antagonistic actionin bone and muscle may be useful agents for the treatment of prostatecancer, either alone or as an adjunct to traditional ADT such as with aGnRH agonist/antagonist [See also A. Stoch, et al., J. Clin. Endocrin.Metab., 86: 2787-2791 (2001)].

[0007] There is a need for more effective agents to treat osteopenia andosteoporosis in both men and women. Osteoporosis is characterized bybone loss, resulting from an imbalance between bone resorption(destruction) and bone formation, which starts in the fourth decade andcontinues throughout life at the rate of about 1-4% per year [Eastell,“Treatment of postmenopausal osteoporosis,” New Engl. J. Med., 338: 736(1998)]. In the United States, there are currently about 20 millionpeople with detectable fractures of the vertebrae due to osteoporosis.In addition, there are about 250,000 hip fractures per year due toosteoporosis, associated with a 12%-20% mortality rate within the firsttwo years, while 30% of patients require nursing home care after thefracture and many never become fully ambulatory again. In postmenopausalwomen, estrogen deficiency leads to increased bone resorption resultingin bone loss in the vertebrae of around 5% per year, immediatelyfollowing menopause. Thus, first line treatment/prevention of thiscondition is inhibition of bone resorption by bisphosphonates,estrogens, selective estrogen receptor modulators (SERMs), andcalcitonin. However, inhibitors of bone resorption are not sufficient torestore bone mass for patients who have already lost a significantamount of bone. The increase in spinal BMD attained by bisphosphonatetreatment can reach 11% after 7 years of treatment with alendronate. Inaddition, as the rate of bone turnover differs from site to site, higherin the trabecular bone of the vertebrae than in the cortex of the longbones, the bone resorption inhibitors are less effectivein increasinghip BMD and preventing hip fracture. Therefore, osteoanabolic agents,which increase cortical bone formation and bone mass of long bones bystimulating periosteal bone formation, would address an unmet need inthe treatment of osteoporosis especially for patients with high risk ofhip fractures. The osteoanabolic agents also complement the boneresorption inhibitors that target the trabecular envelope, leading to abiomechanically favorable bone structure (Schmidt, et al., “Anabolicsteroid: Steroid effects on bone in women,” In: J. P. Bilezikian, etal., Ed., Principles of Bone Biology, San Diego: Academic Press, 1996).Tissue-selective AR agonists with diminished deleterious effects on thecardiovascular system and limited virilizing potential may be useful asa monotherapy for the prevention and/or treatment of femaleosteoporosis. In addition, a compound with osteoanabolic properties inbone and muscle but with reduced activity in the prostate and sexaccessory tissues may be useful for the prevention and/or treatment ofmale osteoporosis and osteopenia in men, particularly elderly men.

[0008] Selective androgen receptor modulators may also be useful totreat certain hematopoietic disorders. It is known that androgensstimulate renal hypertrophy and erythropoietin (EPO) production. Priorto the introduction of recombinant human EPO, androgens were employed totreat anemia caused by chronic renal failure. In addition, androgens atpharmacological doses were found to increase serum EPO levels in anemicpatients with non-severe aplastic anemia and myelodysplastic syndromesbut not in non-anemic patients. Treatment modalities for anemia willrequire selective action such as may be provided by selective androgenreceptor modulators.

[0009] Non-steroidal compounds having androgen receptor modulatingproperties were disclosed in U.S. Pat. Nos. 5,688,808; 5,696,130;6,017,924; 6,093,821; WO 01/16139 (published 8 Mar. 2001); and WO01/16108 (published 8 Mar. 2001), all assigned to LigandPharmaceuticals, and in WO 01/27086, assigned to Kaken Pharm. Co.Additional background for the rationale behind the development ofSelective Androgen Receptor Modulators is found in L. Zhi and E.Martinborough in Ann. Rep. Med. Chem. 36: 169-180 (2001). Non-steroidalSARMs were disclosed in J. P. Edwards, “New Nonsteroidal AndrogenReceptor Modulators Based on4-(Trifluoromethyl)-2(1H)-Pyrrolidino[3,2-g]quinolinone,” Bioorg. Med.Chem. Lett., 8: 745-750 (1998) and in L. Zhi et al., “Switching AndrogenReceptor Antagonists to Agonists by Modifying C-ring Substituents onPiperidino[3,4-g]quinolinone,” Bioorg. Med. Chem. Lett., 9: 1009-1012(1999).

[0010] There exists a need in the clinical art for more effective agentsthat can elicit the positive responses of androgen replacement therapybut without the undesired side effects of non-tissue selective agonistsof the AR. What is needed are compounds that can produce the samepositive responses as androgen replacement therapy but without theundesired side effects. Also needed are androgenic compounds that exertselective effects on different tissues of the body. In this invention,we have identified compounds that function as selective androgenreceptor modulators (SARMs) using a series of in vitro cell-assays thatprofile ligand mediated activation of AR, such as (i) N-C interaction,(ii) transcriptional repression, and (iii) transcriptional activation.SARM compounds in this invention, identified with the methods listedabove, exhibit tissue selective AR agonism in vivo, i.e. agonism in bone(stimulation of bone formation in a rodent model of osteoporosis) andantagonism in prostate (minimal effects on prostate growth in castratedrodents and antagonism of prostate growth induced by AR agonists).

[0011] The compounds of the present invention identified as SARMs areuseful to treat diseases or conditions caused by androgen deficiencywhich can be ameliorated by androgen administration. Such compounds areideal for the treatment of osteoporosis in women and men as amonotherapy or in combination with inhibitors of bone resorption, suchas bisphosphonates, estrogens, SERMs, cathepsin K inhibitors, αvβ3integrin receptor antagonists, calcitonin, and proton pump inhibitors.They can also be used with agents that stimulate bone formation, such asparathyroid hormone or analogs thereof. The SARM compounds of thepresent invention may also be employed for treatment of prostatedisease, such as prostate cancer and benign prostatic hyperplasia (BPH).Moreover, compounds of this invention exhibit minimal effects on skin(acne and facial hair growth) and may be useful for treatment ofhirsutism. Additionally, compounds of this invention can stimulatemuscle growth and may be useful for treatment of sarcopenia and frailty.Moreover, compounds of this invention can exhibit androgen agonism inthe central nervous system and may be useful to treat vasomotor symptoms(hot flush) and to increase energy and libido, particularly inpostmenopausal women. The compounds of the present invention may be usedin the treatment of prostate cancer, either alone or as an adjunct totraditional GnRH agonist/antagonist therapy, for their ability torestore bone, or as a replacement for antiandrogen therapy because oftheir ability to antagonize androgen in the prostate, and minimize bonedepletion in the skeletal system. Further, the compounds of the presentinvention may be used for their ability to restore bone in the treatmentof pancreatic cancer as an adjunct to treatment with antiandrogen, or asmonotherapy for their antiandrogenic properties, offering the advantageover traditional antiandrogens of being bone-sparing. Additionally,compounds of this invention can increase the number of blood cells, suchas red blood cells and platelets, and may be useful for the treatment ofhematopoietic disorders, such as aplastic anemia. Finally, compounds ofthis invention have minimal effects on lipid metabolism. Thus,considering their tissue selective androgen receptor agonism listedabove, the compounds of this invention are ideal for hormone replacementtherapy in hypogonadic (androgen deficient) men.

[0012] It is therefore an object of the present invention to provideandrostane 17β-carboxamide derivatives which are useful as selectiveandrogen receptor modulators.

[0013] It is another object of the present invention to providepharmaceutical compositions comprising the compounds of the presentinvention in association with a pharmaceutically acceptable carrier.

[0014] It is another object of the present invention to providepharmaceutical compositions comprising the steroid derivatives for useas selective androgen receptor modulators.

[0015] It is another object of the present invention to provide methodsfor the treatment of diseases or conditions caused by androgendeficiency which can be ameliorated by androgen administration.

[0016] It is another object of the present invention to provide methodsfor the treatment of diseases or conditions caused by androgendeficiency which can be ameliorated by androgen administration incombination with other agents.

[0017] It is another object of the present invention to provideandrostane 17β-carboxamide derivatives of the present invention andtheir pharmaceutical compositions for use as a medicament for thetreatment of diseases or conditions caused by androgen deficiency whichcan be ameliorated by androgen administration.

[0018] It is another object of the present invention to provideandrostane 17β-carboxamide derivatives of the present invention andtheir pharmaceutical compositions for the manufacture of a medicamentfor the treatment of diseases or conditions caused by androgendeficiency which can be ameliorated by androgen administration.

[0019] These and other objects will become readily apparent from thedetailed description which follows.

SUMMARY OF THE INVENTION

[0020] The present invention provides a method for modulating a functionmediated by the androgen receptor in a tissue selective manner in apatient in need of such modulation, comprising administering to thepatient a therapeutically effective amount of a compound of structuralformula I:

[0021] or a pharmaceutically acceptable salt thereof;

[0022] wherein

[0023] “a” represents a single bond or a double bond;

[0024] R¹ is selected from the group consisting of

[0025] hydrogen,

[0026] C₁₋₃ alkyl,

[0027] C₃₋₆ cycloalkyl,

[0028] phenyl, and

[0029] phenyl C₁₋₃ alkyl;

[0030] in which alkyl, cycloalkyl, and phenyl are unsubstituted orsubstituted with one to three groups independently selected fromhalogen, hydroxy, amino, carboxy, and C₁₋₄ alkoxy;

[0031] R² and R³ are each independently selected from the groupconsisting of

[0032] hydrogen,

[0033] C₁₋₆ alkyl,

[0034] C₂₋₆ alkenyl,

[0035] C₂₋₆ alkynyl,

[0036] C₃₋₆ cycloalkyl,

[0037] hydroxy,

[0038] C₁₋₄ alkoxy,

[0039] halogen,

[0040] halogen C₁₋₄ alkyl,

[0041] carboxy,

[0042] C₁₋₆ alkylcarbonyl,

[0043] C₁₋₆ alkyloxycarbonyl,

[0044] C₁₋₆ alkylcarbonyloxy,

[0045] (C₁₋₆)₀₋₂aminocarbonyloxy,

[0046] in which alkyl, alkenyl, alkynyl, and cycloalkyl areunsubstituted or substituted with one to three substituentsindependently selected from halogen, hydroxy, carboxy, and C₁₋₄ alkoxy;or R² and R³ are taken together with the carbon atom to which they areattached to form a carbonyl group, a C₁₋₆ alkylidene group, or aspiro-C₃₋₆ cycloalkyl group, unsubstituted or substituted with C₁₋₄alkyl; or R² and R7 are taken together with the carbon atoms to whichthey are attached to form a cyclopropyl group;

[0047] R⁴ is hydrogen or C₁₋₄ alkyl;

[0048] R⁵ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, and phenyl C₁₋₃ alkyl;

[0049] R⁶ is aryl wherein the aryl group is selected from the groupconsisting of

[0050] (1) phenyl,

[0051] (2) naphthyl,

[0052] (3) benzimidazolyl,

[0053] (4) benzofuranyl,

[0054] (5) benzothiophenyl,

[0055] (6) benzoxazolyl,

[0056] (7) benzothiazolyl,

[0057] (8) benzodihydrofuranyl,

[0058] (9) indolyl,

[0059] (10) quinolyl,

[0060] (11) isoquinolyl,

[0061] (12) furanyl,

[0062] (13) thienyl,

[0063] (14) imidazolyl,

[0064] (15) oxazolyl,

[0065] (16) thiazolyl,

[0066] (17) isoxazolyl,

[0067] (18) isothiazolyl,

[0068] (19) pyrazolyl,

[0069] (20) pyrrolyl,

[0070] (21) pyridyl,

[0071] (22) pyrimidyl,

[0072] (23) pyrazinyl,

[0073] (24) thiadiazolyl,

[0074] (25) oxadiazolyl,

[0075] (26) triazolyl, and

[0076] (27) tetrazolyl;

[0077] wherein the aryl group as defined above items (1) to (27) isunsubstituted or substituted with one to three substituentsindependently selected from halogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, phenyl, phenyl C₁₋₃ alkyl, amino, amino C₁₋₆ alkyl,C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₆ alkyl, C₁₋₆ alkylamino, di-(C₁₋₆alkyl)amino, di-(C₁₋₆ alkyl)amino C₁₋₆ alkyl, C₁₋₆ alkylamino C₁₋₆alkyl, aminocarbonylamino, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, C₁₋₄alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfonylamino, carboxy, carboxy C₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl,C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, C₁₋₅ alkylcarbonyloxy, hydroxy, hydroxyC₁₋₆ alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, andtrifluoroethoxy; and

[0078] R⁷ is hydrogen or C₁₋₄ alkyl.

[0079] The present invention is also concerned with a method ofactivating the function of the androgen receptor in a patient, and, inparticular, a method wherein the function of the androgen receptor isactivated (agonized) in bone and/or muscle tissue and blocked in theprostate of a male patient or in the uterus of a female patient with acompound of structural formula I. The compounds of formula I are usefulin the prevention and/or treatment of diseases or conditions caused byandrogen deficiency or which can be ameliorated by androgen replacement.These diseases or conditions include osteoporosis, periodontal disease,bone fracture, bone damage following bone reconstructive surgery,sarcopenia, frailty, aging skin, male hypogonadism, post-menopausalsymptoms in women, atherosclerosis, hypercholesterolemia,hyperlipidemia, aplastic anemia and other hematopoietic disorders,pancreatic cancer, inflammatory arthritis and joint repair. Thecompounds of the present invention may be used alone or in combinationwith other active agents. In particular, the compounds of the presentinvention are useful for the prevention and/or treatment of male andfemale osteoporosis.

[0080] The present invention is also concerned with novel compoundswhich are selective androgen receptor modulators, pharmaceuticalcompositions containing these novel compounds in association with apharmaceutically acceptable carrier, and methods to treat diseases orconditions caused by androgen deficiency or which can be ameliorated byandrogen replacement with the novel compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0081] The present invention provides a method for modulating a functionmediated by the androgen receptor in a tissue selective manner in apatient in need of such modulation, comprising administering to thepatient a therapeutically effective amount of a compound of structuralformula I:

[0082] or a pharmaceutically acceptable salt thereof;

[0083] wherein

[0084] “a” represents a single bond or a double bond;

[0085] R¹ is selected from the group consisting of

[0086] hydrogen,

[0087] C₁₋₃ alkyl,

[0088] C₃₋₆ cycloalkyl,

[0089] phenyl, and

[0090] phenyl C₁₋₃ alkyl;

[0091] in which alkyl, cycloalkyl, and phenyl are unsubstituted orsubstituted with one to three groups independently selected fromhalogen, hydroxy, amino, carboxy, and C₁₋₄ alkoxy;

[0092] R² and R³ are each independently selected from the groupconsisting of

[0093] hydrogen,

[0094] C₁₋₆ alkyl,

[0095] C₂₋₆ alkenyl,

[0096] C₂₋₆ alkynyl,

[0097] C₃₋₆ cycloalkyl,

[0098] hydroxy,

[0099] C₁₋₁₄ alkoxy,

[0100] halogen,

[0101] halogen C₁₋₄ alkyl,

[0102] carboxy,

[0103] C₁₋₆ alkylcarbonyl,

[0104] C₁₋₆ alkyloxycarbonyl,

[0105] C₁₋₆ alkylcarbonyloxy,

[0106] (C₁₋₆)₀₋₂aminocarbonyloxy,

[0107] in which alkyl, alkenyl, alkynyl, and cycloalkyl areunsubstituted or substituted with one to three substituentsindependently selected from halogen, hydroxy, carboxy, and C₁₋₄ alkoxy;or R² and R³ are taken together with the carbon atom to which they areattached to form a carbonyl group, a C₁₋₆ alkylidene group, or aspiro-C₃₋₆ cycloalkyl group, unsubstituted or substituted with C₁₋₄alkyl; or R² and R⁷ are taken together with the carbon atoms to whichthey are attached to form a cyclopropyl group;

[0108] R⁴ is hydrogen or C₁₋₄ alkyl;

[0109] R⁵ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, and phenyl C₁₋₃ alkyl;

[0110] R⁶ is aryl wherein the aryl group is selected from the groupconsisting of

[0111] (1) phenyl,

[0112] (2) naphthyl,

[0113] (3) benzimidazolyl,

[0114] (4) benzofuranyl,

[0115] (5) benzothiophenyl,

[0116] (6) benzoxazolyl,

[0117] (7) benzothiazolyl,

[0118] (8) benzodihydrofuranyl,

[0119] (9) indolyl,

[0120] (10) quinolyl,

[0121] (11) isoquinolyl,

[0122] (12) furanyl,

[0123] (13) thienyl,

[0124] (14) imidazolyl,

[0125] (15) oxazolyl,

[0126] (16) thiazolyl,

[0127] (17) isoxazolyl,

[0128] (18) isothiazolyl,

[0129] (19) pyrazolyl,

[0130] (20) pyrrolyl,

[0131] (21) pyridyl,

[0132] (22) pyriridyl,

[0133] (23) pyrazinyl,

[0134] (24) thiadiazolyl,

[0135] (25) oxadiazolyl,

[0136] (26) triazolyl, and

[0137] (27) tetrazolyl;

[0138] wherein the aryl group as defined above items (1) to (27) isunsubstituted or substituted with one to three substituentsindependently selected from halogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, phenyl, phenyl C₁₋₃ alkyl, amino, amino C₁₋₆ alkyl,C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₆ alkyl, C₁₋₆ alkylamino, di-(C₁₋₆alkyl)amino, di-(C₁₋₆ alkyl)amino C₁₋₆ alkyl, C₁₋₆ alkylamino C₁₋₆alkyl, aminocarbonylamino, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, C₁₋₄alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfonylamino, carboxy, carboxy C₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl,C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, C₁₋₅ alkylcarbonyloxy, hydroxy, hydroxyC₁₋₆ alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, andtrifluoroethoxy; and

[0139] R⁷ is hydrogen or C₁₋₄ alkyl.

[0140] In one embodiment of the compounds useful in the methods of thepresent invention, “a” represents a double bond and R⁷ is hydrogen ormethyl. In a class of this embodiment, R¹ is hydrogen or C₁₋₃ alkyl.

[0141] In a second embodiment of the compounds useful in the methods ofthe present invention, R⁴ is hydrogen.

[0142] In a third embodiment of the compounds useful in the methods ofthe present invention, R⁵ is hydrogen or methyl and R⁶ is selected fromthe group consisting of phenyl, naphthyl, and pyridyl, unsubstituted orsubstituted with one to three groups independently selected fromhalogen, nitro, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, and cyano. Ina class of this embodiment, R⁶ is phenyl, unsubstituted or substitutedwith one to three groups independently selected from halogen, nitro,trifluoromethyl, methyl, methoxy, and cyano.

[0143] In a fourth embodiment of the compounds useful in the methods ofthe present invention, R² and R³ are each hydrogen or are taken togetherwith the carbon to which they are attached to form a spirocyclopropyl ora methylene group.

[0144] In a fifth embodiment of the compounds useful in the methods ofthe present invention, R² and R⁷ are taken together with the carbonatoms to which they are attached to form a fused cyclopropyl ring.

[0145] In yet a further embodiment of the compounds useful in themethods of the present invention are those represented by structuralformula II:

[0146] or a pharmaceutically acceptable salt thereof; wherein

[0147] R² and R³ are hydrogen or R² and R³ are taken together with thecarbon atom to which they are attached to form a methylene or aspirocyclopropyl group;

[0148] R⁵ is hydrogen or methyl;

[0149] R⁶ is phenyl, naphthyl, or pyridyl, unsubstituted or substitutedwith one to three groups independently selected from halogen, C₁₋₄alkyl, amino, C₁₋₃ acylamino, C₁₋₄ alkylamino, di-(C₁₋₄ alkyl)amino,C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfonylamino, carboxy, C₁₋₅ alkoxycarbonyl, C₁₋₅ alkylcarbonyloxy,hydroxy, cyano, nitro, and trifluoromethyl; and

[0150] R⁷ is hydrogen or methyl.

[0151] Illustrative but non-limiting examples of compounds useful in themethods of the present invention are the following:

[0152](17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0153](17β)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0154](17β)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0155] (17β)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0156] (17β)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0157] (17β)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0158] (17β)-3-oxo-N-phenylandrost-4-ene-17-carboxamide;

[0159] (17β)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0160] (17β)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0161] (17β)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0162] (17β)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0163] (17β)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0164] (17β)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0165] (17β)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0166] (17β)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0167] (17β)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0168] (17β)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0169] (17β)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0170](17β)-N-(3-methoxy-5-trfluoromethylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0171](17β)-N-methyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;

[0172](17β)-N-ethyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;

[0173](17β)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0174](17β)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0175](17β)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0176](17β)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxamide;

[0177](17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0178](17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;and

[0179](17β)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0180] or a pharmaceutically acceptable salt thereof.

[0181] Further illustrative but non-limiting examples of compoundsuseful in the methods of the present invention are the following:

[0182] (1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide

[0183] and

[0184] (1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide.

[0185] The present invention also provides the following novel compoundswhich are useful as selective androgen receptor modulators:

[0186](17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0187](17β)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0188](17β)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0189] (17β)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0190] (17β)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0191] (17β)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0192] (17β)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0193] (17β)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0194] (17β)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0195] (17β)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0196] (17β)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0197] (17β)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0198] (17β)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0199] (17β)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0200] (17β)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0201] (17β)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0202] (17β)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0203](17β)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-carboxamide;

[0204](17β)-N-methyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;

[0205](17β)-N-ethyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;

[0206](17β)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0207](17β)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0208](17β)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0209](17β)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxamide;

[0210](17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0211](17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0212](17β)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;

[0213] (1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;and

[0214] (1aS,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;

[0215] or a pharmaceutically acceptable salt thereof.

[0216] The term “alkyl” shall mean straight or branched chain alkanes ofone to ten total carbon atoms, or any number within this range (i.e.,methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). Theterm “C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence ofan alkyl group.

[0217] The term “alkenyl” shall mean straight or branched chain alkenesof two to ten total carbon atoms, or any number within this range.

[0218] The term “alkynyl” shall mean straight or branched chain alkynesof two to ten total carbon atoms, or any number within this range.

[0219] The term “alkylidene” shall mean a straight or branched chainalkylidene group of one to ten total carbon atoms, or any number withinthis range.

[0220] The term “cycloalkyl” shall mean cyclic rings of alkanes of threeto eight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl).

[0221] The term “cycloheteroalkyl,” as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groupsinclude, but are not limited to, piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, and piperazinyl. In one embodiment of the presentinvention, cycloheteroalkyl is selected from piperidinyl, pyrrolidinyl,and morpholinyl.

[0222] The term “alkoxy,” as used herein, refers to straight or branchedchain alkoxides of the number of carbon atoms specified (e.g., C₁₋₅alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).

[0223] The term “aryl,” as used herein, refers to a monocyclic orbicyclic system comprising at least one aromatic ring, wherein themonocylic or bicyclic system contains 0, 1, 2, 3, or 4 heteroatomschosen from N, O, or S, and wherein the monocylic or bicylic system iseither unsubstituted or substituted with one or more groupsindependently selected from halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloheteroalkyl, aryl C₁₋₆alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl,(aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkylthio, aryl C₀₋₆alkylthio,C₁₋₆ alkylsulfinyl, aryl C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₀₋₆alkylsulfonyl, C₁₋₆ alkoxy C₀₋₆alkyl, aryl C₀₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, aryl C₀₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, aryl C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, aryl C₀₋₆alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, aryl C₀₋₆ alkoxycarbonylamino,C₁₋₆alkylaminocarbonylamino, aryl C₀₋₆alkylaminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonylamino, (aryl C₀₋₆alkyl)₂ aminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonyloxy, and (aryl C₀₋₆alkyl)₂ aminocarbonyloxy.Examples of aryl include, but are not limited to, phenyl, naphthyl,pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl,dihydrobenzofuryl, benzo(1,3)dioxolanyl, benzo(1,4)dioxanyl, oxazolyl,isoxazolyl, thiazolyl, quinolinyl, and isothiazolyl, which are eitherunsubstituted or substituted with one or more groups independentlyselected from halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl C₁₋₆alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl,(aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkylthio, aryl C₀₋₆alkylthio,C₁₋₆ alkylsulfinyl, aryl C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₀₋₆alkylsulfonyl, C₁₋₆ alkoxy C₀₋₆alkyl, aryl C₀₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, aryl C₀₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, aryl C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamnino, aryl C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, aryl C₀₋₆alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, aryl C₀₋₆ alkoxycarbonylamino,C₁₋₆alkylaaminocarbonylamino, aryl C₀₋₆alkylaminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonylamino, (aryl C₀₋₆alkyl)₂ aminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonyloxy, and (aryl C₀₋₆alkyl)₂ aminocarbonyloxy.In one embodiment of the present invention, aryl is selected fromphenyl, pyridyl, pyrazolyl, benzamidazolyl, imidazolyl, furyl, napthyl,indolyl, and quinolinyl. Preferably, the aryl group is unsubstituted,mono-, di-, or tri- substituted with one to three of the above-namedsubstituents; more preferably, the aryl group is unsubstituted, mono- ordi-substituted with one to two of the above-named substituents.

[0224] Whenever the term “alkyl” or “aryl” or either of their prefixroots appears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), itshall be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈)shall refer independently to the number of carbon atoms in an alkyl orcyclic alkyl moiety or to the alkyl portion of a larger substituent inwhich alkyl appears as its prefix root.

[0225] The terms “arylalkyl” and “alkylaryl” include an alkyl portionwhere alkyl is as defined above and include an aryl portion where arylis as defined above. Examples of arylalkyl include, but are not limitedto, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, andthienylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

[0226] The term “halogen” shall include iodine, bromine, chlorine, andfluorine.

[0227] The term “oxy” means an oxygen (O) atom. The term “thio” means asulfur (S) atom. The term “oxo” means “═O”. The term “carbonyl” means“C═O.”

[0228] The term “substituted” shall be deemed to include multipledegrees of substitution by a named substitutent. Where multiplesubstituent moieties are disclosed or claimed, the substituted compoundcan be independently substituted by one or more of the disclosed orclaimed substituent moieties, singly or plurally. By independentlysubstituted, it is meant that the (two or more) substituents can be thesame or different.

[0229] When any variable (e.g., R³, R⁴, etc.) occurs more than one timein any substituent or in formula I, its definition in each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

[0230] Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

[0231] In choosing compounds of the present invention, one of ordinaryskill in the art will recognize that the various substituents, i.e. R¹,R², R³, etc., are to be chosen in conformity with well-known principlesof chemical structure connectivity.

[0232] Compounds of the present invention have been found to betissue-selective modulators of the androgen receptor (SARMs). In oneaspect, compounds of the present invention may be useful to activate thefunction of the androgen receptor in a patient, and in particular toactivate the function of the androgen receptor in bone and/or muscletissue and block or inhibit (“antagonize”) the function of the androgenreceptor in the prostate of a male patient or in the uterus of a femalepatient. The activation of the AR in bone can be assayed throughstimulation of bone formation in a rodent model of osteoporosis, and theantagonism of the AR in the prostate can be assayed through observationof minimal effects on prostate growth in castrated rodents andantagonism of prostate growth induced by AR agonists, as detailed in theExamples. A further aspect of the present invention is concerned withcompounds of structural formula I that block the function of theandrogen receptor in the prostate of a male patient or in the uterus ofa female patient induced by AR agonists, but not in hair-growing skin orvocal cords, and activate the function of the androgen receptor in boneand/or muscle tissue, but not in organs which control blood lipid levels(e.g. liver).

[0233] The compounds of the present invention may be used to treatand/or prevent conditions in a male subject which are caused by androgendeficiency or which can be ameliorated by androgen replacement,including, but not limited to osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, bone fracture,bone damage following bone reconstructive surgery, sarcopenia, frailty,aging skin, male hypogonadism, post-menopausal symptoms in women,atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemiaand other hematopoietic disorders, inflammatory arthritis and jointrepair, HIV-wasting, cancer cachexia, muscular dystrophies, prematureovarian failure, and autoimmune disaease, alone or in combination withother active agents. Treatment is effected by administration of atherapeutically effective amount of the compound of structural formula Ito a patient in need of such treatment.

[0234] In one embodiment, the compounds of the present invention may beused to treat and/or prevent conditions in a male subject which arecaused by androgen deficiency or which can be ameliorated by androgenreplacement, including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,cancer cachexia, aplastic and other anemias, and muscular dystrophies,alone or in combination with other active agents. Treatment is effectedby administration of a therapeutically effective amount of the compoundof structural formula I to a male patient in need of such treatment.

[0235] In another embodiment, the compounds of the present invention maybe used to treat and/or prevent conditions in a female subject which arecaused by androgen deficiency or which can be ameliorated by androgenreplacement, including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,cancer cachexia, aplastic and other anemias, muscular dystrophies,premature ovarian failure, and autoimmune disease, alone or incombination with other active agents. Treatment is effected byadministration of a therapeutically effective amount of the compound ofstructural formula I to a female patient in need of such treatment.

[0236] The compounds of structural formula I may also be employed asadjuncts to traditional androgen depletion therapy in the treatment ofprostate cancer to restore bone, minimize bone loss, and maintain bonemineral density. In this manner, they may be employed together withtraditional androgen deprivation therapy, including GnRHagonists/antagonists, such as those disclosed in P. Limonta, et al.,“LHRH analogues as anticancer agents: pituitary and extrapituitary sitesof action,” Exp. Opin. Invest. Drugs, 10: 709-720 (2001); H. J.Stricker, “Luteinizing hormone-releasing hormone antagonists,” Urology,58 (Suppl. 2A): 24-27 (2001); R. P. Millar, et al., “Progress towardsthe development of non-peptide orally-active GnRH antagonists,” BritishMedical Bulletin, 56: 761-772 (2000); and A. V. Schally et al.,“Rational use of agonists and antagonists of LH-RH in the treatment ofhormone-sensitive neoplasms and gynecologic conditions,” Advanced DrugDelivery Reviews, 28: 157-169 (1997). It is also possible that thecompounds of structural formula I may be used in combination withantiandrogens, such as flutamide, 2-hydroxyflutamide (the activemetabolite of flutamide), nilutamide, and bicalutamide (Casodex™) in thetreatment of prostate cancer.

[0237] Further, the compounds of the present invention may also beemployed in the treatment of pancreatic cancer, either for theirandrogen antagonist properties or as an adjunct to an antiandrogen, suchas flutamide, 2-hydroxyflutamide (the active metabolite of flutamide),nilutamide, and bicalutamide (Casodex™).

[0238] Compounds of structural formula I have minimal negative effectson lipid metabolism. Therefore, considering their tissue selectiveandrogen agonistic properties, the compounds of this invention haveadvantages over existing approaches for hormone replacement therapy inhypogonadic (androgen deficient) men.

[0239] Additionally, compounds of the present invention can increase thenumber of blood cells, such as red blood cells and platelets, and can beused for treatment of hematopoietic disorders, such as aplastic anemia.

[0240] Representative compounds of the present invention typicallydisplay submicromolar binding affinity for the androgen receptor.Compounds of this invention are therefore useful in treating mammalssuffering from disorders related to androgen receptor function.Pharmacologically effective amounts of the compound, including thepharmaceutically effective salts thereof, are administered to themammal, to treat disorders related to androgen receptor function, orwhich can be improved by the addition of additional androgen, such asosteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, aplastic anemia and otherhematopoietic disorders, pancreatic cancer, inflammatory arthritis andjoint repair.

[0241] It is generally preferable to administer compounds of the presentinvention in their enantiomerically pure form. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

[0242] As used herein, a compound of the present invention whichfunctions as an “agonist” of the androgen receptor can bind to theandrogen receptor and initiate a physiological or a pharmacologicalresponse characteristic of that receptor. The term “tissue-selectiveandrogen receptor modulator” refers to an androgen receptor ligand thatmimics the action of a natural ligand in some tissues but not in others.A “partial agonist” is an agonist which is unable to induce maximalactivation of the receptor population, regardless of the amount ofcompound applied. A “full agonist” induces full activation of theandrogen receptor population at a given concentration. A compound of thepresent invention which functions as an “antagonist” of the androgenreceptor can bind to the androgen receptor and block or inhibit theandrogen-associated responses normally induced by a natural androgenreceptor ligand.

[0243] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases and inorganic or organic acids.Salts derived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabarine, isopropylarine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobrornine, triethylamine, trimethylarine,tripropylamine, tromethamine, and the like.

[0244] When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

[0245] The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

[0246] The term “composition” as used herein is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0247] By “pharmaceutically acceptable” it is meant that the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not be deleterious to the recipient thereof.

[0248] The terms “administration of a compound” and “administering acompound” should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need of treatment.

[0249] The administration of the compound of structural formula I inorder to practice the present methods of therapy is carried out byadministering an effective amount of the compound of structural formulaI to the patient in need of such treatment or prophylaxis. The need fora prophylactic administration according to the methods of the presentinvention is determined via the use of well-known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration, other drugs and treatments which the patientmay concomitantly require, and other factors in the physician'sjudgment.

[0250] Generally, the daily dosage of the compound of structural formulaI may be varied over a wide range from 0.01 to 1000 mg per adult humanper day. Most preferably, dosages range from 0.1 to 200 mg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175,180, 200, 225, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated.

[0251] The dose may be administered in a single daily dose or the totaldaily dosage may be administered in divided doses of two, three or fourtimes daily. Furthermore, based on the properties of the individualcompound selected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

[0252] When administered via intranasal routes, transdermal routes, byrectal or vaginal suppositories, or through an intravenous solution, thedosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0253] Exemplifying the invention is a pharmaceutical compositioncomprising any of the compounds described above and a pharmaceuticallyacceptable carrier. Also exemplifying the invention is a pharmaceuticalcomposition made by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

[0254] Formulations of the tissue-selective androgen receptor modulatoremployed in the present method for medical use comprise the compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not being deleterious to therecipient subject of the formulation.

[0255] The present invention, therefore, further provides apharmaceutical formulation comprising the compound of structural formulaI together with a pharmaceutically acceptable carrier thereof.

[0256] The formulations include those suitable for oral, rectal,intravaginal, topical or parenteral (including subcutaneous,intramuscular and intravenous administration). Preferred formulationsare those suitable for oral administration.

[0257] The formulations may be presented in a unit dosage form and maybe prepared by any of the methods known in the art of pharmacy. Allmethods include the step of bringing the active compound in associationwith a carrier which constitutes one or more ingredients. In general,the formulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into the desired dosage form.

[0258] Formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, tablets or lozenges, each containing a predetermined amount ofthe active compound; as a powder or granules; or a suspension orsolution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, anelixir, or an emulsion.

[0259] A tablet may be made by compression or molding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets may be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

[0260] Oral liquid forms, such as syrups or suspensions in suitablyflavored suspending or dispersing agents such as the synthetic andnatural gums, for example, tragacanth, acacia, methyl cellulose and thelike, may be made by adding the active compound to the solution orsuspension. Additional dispersing agents which may be employed includeglycerin and the like.

[0261] Formulations for vaginal or rectal administration may bepresented as a suppository with a conventional carrier, i.e., a basethat is nontoxic and nonirritating to mucous membranes, compatible withthe compound of structural formula I, and is stable in storage and doesnot bind or interfere with the release of the compound of structuralformula I. Suitable bases include: cocoa butter (theobroma oil),polyethylene glycols (such as carbowax and polyglycols),glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyethylenesorbitan fatty acid esters (such as Tween, Myrj, and Arlacel),glycerinated gelatin, and hydrogenated vegetable oils. When glycerinatedgelatin suppositories are used, a preservative such as methylparaben orpropylparaben may be employed.

[0262] Topical preparations containing the active drug component can beadmixed with a variety of carrier materials well known in the art, suchas, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

[0263] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[0264] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-inked linked or amphipathic block copolymers of hydrogels.

[0265] Formulations suitable for parenteral administration includeformulations that comprise a sterile aqueous preparation of the activecompound which is preferably isotonic with the blood of the recipient.Such formulations suitably comprise a solution or suspension of acompound that is isotonic with the blood of the recipient subject. Suchformulations may contain distilled water, 5% dextrose in distilled wateror saline and the active compound. Often it is useful to employ apharmaceutically and pharmacologically acceptable acid addition salt ofthe active compound that has appropriate solubility for the solventsemployed. Useful formulations also comprise concentrated solutions orsolids comprising the active compound which on dilution with anappropriate solvent give a solution suitable for parenteraladministration.

[0266] The compounds of the present invention may be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug, for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

[0267] The pharmaceutical composition and method of the presentinvention may further comprise other therapeutically active compoundsusually applied in the treatment and prevention of the above mentionedconditions, including osteoporosis, periodontal disease, bone fracture,bone damage following bone reconstructive surgery, sarcopenia, frailty,aging skin, male hypogonadism, post-menopausal symptoms in women,atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemiaand other hematopoietic disorders, pancreatic cancer, inflammatoryarthintis, and joint repair.

[0268] For the treatment and prevention of osteoporosis, the compoundsof the present invention may be administered in combination with abone-strengthening agent selected from antiresorptive agents,osteoanabolic agents, and other agents beneficial for the skeletonthrough mechanisms which are not precisely defined, such as calciumsupplements, flavonoids, and vitamin D analogs. The conditions ofperiodontal disease, bone fracture, and bone damage following bonereconstructive surgery may also benefit from these combined treatments.For example, the compounds of the instant invention may be effectivelyadministered in combination with effective amounts of other agents suchas estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, αvβ3integrin receptor antagonists, vacuolar ATPase inhibitors, thepolypeptide osteoprotegerin, antagonists of VEGF, thiazolidinediones,calcitonin, protein kinase inhibitors, parathyroid hormone (PTH andanalogs, calcium receptor antagonists, growth hormone secretagogues,growth hormone releasing hormone, insulin-like growth factor, bonemorphogenetic protein (BMP), inhibitors of BMP antagonism, prostaglandinderivatives, fibroblast growth factors, vitamin D and derivativesthereof, vitamin K and derivatives thereof, soy isoflavones, calciumsalts, and fluoride salts. The conditions of periodontal disease, bonefracture, and bone damage following bone reconstructive surgery may alsobenefit from these combined treatments. In one embodiment of the presentinvention, a compound of the instant invention may be effectivelyadministered in combination with an effective amount of abone-strengthening agent selected from the group consisting of estrogenor an estrogen derivative, alone or in combination with a progestin orprogestin derivative; a bisphosphonate; an antiestrogen or a selectiveestrogen receptor modulator; an αvβ3 integrin receptor antagonist; acathepsin K inhibitor; an osteoclast vacuolar ATPase inhibitor;calcitonin; and osteoprotegerin.

[0269] In the treatment of osteoporosis, the activity of the compoundsof the present invention are distinct from that of the anti-resorptiveagents: estrogens, bisphosphonates, SERMs, calcitonin, cathepsin Kinhibitors, vacuolar ATPase inhibitors, agents interfering with theRANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any otherinhibitors of osteoclast generation or osteoclast activation. Ratherthan inhibiting bone resorption, the compounds of structural formula Istimulate bone formation, acting preferentially on cortical bone, whichis responsible for a significant part of bone strength. The thickeningof cortical bone substantially contributes to a reduction in fracturerisk, especially fractures of the hip. The combination of thetissue-selective androgen receptor modulators of structural formula Iwith anti-resorptive agents such as estrogen, bisphosphonates,antiestrogens, SERMs, calcitonin, αvβ3 integrin receptor antagonists,HMG-CoA reductase inhibitors, vacuolar ATPase inhibitors, and cathepsinK inhibitors is particularly useful because of the complementarity ofthe bone anabolic and antiresorptive actions.

[0270] Bone antiresportive agents are those agents which are known inthe art to inhibit the resorption of bone and include, for example,estrogen and estrogen derivatives which include steroidal compoundshaving estrogenic activity such as, for example, 17β-estradiol, estrone,conjugated estrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol,and the like. The estrogen or estrogen derivative may be employed aloneor in combination with a progestin or progestin derivative. Nonlimitingexamples of progestin derivatives are norethindrone andmedroxy-progesterone acetate.

[0271] Bisphosphonates are also bone anti-resorptive agents.Bisphosphonate compounds which may also be employed in combination witha compound of structural formula I of the present invention include:

[0272] (a) alendronic acid: (4-amino-1-hydroxybutylidene)-bis-phosphonicacid;

[0273] (b) alendronate (also known as alendronate sodium or monosodiumtrihydrate): (4-amino-1-hydroxybutylidene)-bis-phosphonate monosodiumtrihydrate (alendronic acid and alendronate are described in U.S. Pat.No. 4,922,007, to Kieczykowski et al., issued May 1, 1990, and U.S. Pat.No. 5,019,651, to Kieczykowski, issued May 28, 1991, both of which areincorporated by reference herein in their entirety);

[0274] (c) [cycloheptylamino-methylene]-bis-phosphonate (incadronate),which is described in U.S. Pat. No. 4,970,335, to Isomura et al., issuedNov. 13, 1990, which is incorporated by reference herein in itsentirety;

[0275] (d) (dichloromethylene)-bis-phosphonic acid (clodronic acid) andthe disodium salt (clodronate), which are described in Belgium Patent672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which areincorporated by reference herein in their entirety;

[0276] (e) [1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bis-phosphonate(EB-1053);

[0277] (f) (1-hydroxyethylidene)-bis-phosphonate (etidronate);

[0278] (g) [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate(ibandronate), which is described in U.S. Pat. No. 4,927,814, issued May22, 1990, which is incorporated by reference herein in its entirety;

[0279] (h) (6-amino-1hydroxyhexylidene)-bis-phosphonate (neridronate);

[0280] (i) [3-(dimethylamino)-1-hydroxypropylidene]-bis-phosphonate(olpadronate);

[0281] (j) (3-amino-1-hydroxypropylidene)-bis-phosphonate (pamidronate);

[0282] (k) [2-(2-pyridinyl)ethylidene]-bis-phosphonate (piridronate),which is described in U.S. Pat. No. 4,761,406, which is incorporated byreference in its entirety;

[0283] (l) [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate(risedronate);

[0284] (m) {[(4-chlorophenyl)thio]methylene}-bis-phosphonate(tiludronate), which is described in U.S. Pat. No. 4,876,248, toBreliere et al., Oct. 24, 1989, which is incorporated by referenceherein in its entirety;

[0285] (n) [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bis-phosphonate(zoledronate); and

[0286] (o)[1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bis-phosphonate(minodronate).

[0287] Preferred are bisphosphonates selected from the group consistingof alendronate, clodronate, EB-1053, etidronate, ibandronate,incadronate, minodronate, neridronate, olpadronate, pamidronate,piridronate, risedronate, tiludronate, and zoledronate, andpharmaceutically acceptable salts thereof, and mixtures thereof.

[0288] More preferred is alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof.

[0289] Most preferred is alendronate monosodium trihydrate.

[0290] Still further, antiestrogenic compounds such as raloxifene (see,e.g., U.S. Pat. No. 5,393,763), clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11,555A, U-100A, andsalts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) may be employed in combination with a compound of structuralformula I in the methods and compositions of the present invention.These agents are also known as SERMs, or selective estrogen receptormodulators, agents known in the art to prevent bone loss by inhibitingbone resorption via pathways believed to be similar to those ofestrogens. These agents may be used in combination with the compounds ofthe present invention to beneficially treat bone disorders includingosteoporosis. Such agents include, for example, tamoxifen, raloxifene,lasofoxifene, toremifene, azorxifene, EM-800, EM-652, TSE 424,clomiphene, droloxifene, idoxifene, and levormeloxifene [Goldstein, etal., “A pharmacological review of selective oestrogen receptormodulators,” Human Reproduction Update, 6: 212-224 (2000), and Lufkin,et al., “The role of selective estrogen receptor modulators in theprevention and treatment of osteoporosis,” Rheumatic Disease Clinics ofNorth America, 27: 163-185 (2001)]. SERMs are also discussed in“Targeting the Estrogen Receptor with SERMs,” Ann. Rep. Med. Chem. 36:149-158 (2001).

[0291] αvβ3 Integrin receptor antagonists suppress bone resorption andmay be employed in combination with the tissue selective androgenreceptor modulators of structural formula I for the treatment of bonedisorders including osteoporosis. Peptidyl as well as peptidomnimeticantagonists of the αvβ3 integrin receptor have been described both inthe scientific and patent literature. For example, reference is made toW. J. Hoekstra and B. L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) andreferences cited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO97/37655; WO 98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO98/31359; WO 98/30542; WO 99/15506; WO 99/15507; WO 00/03973; EP 853084;EP 854140; EP 854145; U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754;5,741,796; 5,780,426; 5,929,120; 5,952,341; 6,017,925; and 6,048,861.Evidence of the ability of αvβ3 integrin receptor antagonists to preventbone resorption in vitro and in vivo has been presented (see V. W.Engleman et al., “A Peptidomimetic Antagonist of the αvβ3 IntegrinInhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vivo,” J.Clin. Invest. 99: 2284-2292 (1997); S. B. Rodan et al., “A High AffinityNon-Peptide αvβ3 Ligand Inhibits Osteoclast Activity In Vitro and InVivo,” J. Bone Miner. Res. 11: S289 (1996); J. F. Gourvest et al.,“Prevention of OVX-Induced Bone Loss With a Non-peptidic Ligand of theαvβ3 Vitronectin Receptor,” Bone 23: S612 (1998); M. W. Lark et al., “AnOrally Active Vitronectin Receptor αvβ3 Antagonist Prevents BoneResorption In Vitro and In Vivo in the Ovariectomized Rat,” Bone 23:S219 (1998)). Other αvβ3 antagonists are described in R. M. Keenan etal., “Discovery of Potent Nonpeptide Vitronectin Receptor (αvβ3)Antagonists,” J. Med. Chem. 40: 2289-2292 (1997); R. M. Keenan et al.,“Benzimidazole Derivatives As Arginine Mimetics in 1,4-BenzodiazepineNonpeptide Vitronectin Receptor (αvβ3) Antagonists,” Bioorg. Med. Chem.Lett. 8: 3165-3170 (1998); and R. M. Keenan et al., “Discovery of anImidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide VitronectinReceptor (αvβ3) Antagonist With Efficacy in a Restenosis Model,” Bioorg.Med. Chem. Lett. 8: 3171-3176 (1998). Still other benzazepine,benzodiazepine and benzocycloheptene αvβ3 integrin receptor antagonistsare described in the following patent publications: WO 96/00574, WO96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO97/24124, WO 98/14192, WO 98/15278, WO 99/05107, WO 99/06049, WO99/15170, WO 99/15178, WO 99/15506, and U.S. Pat. No. 6,159,964, and WO97/34865. αvβ3 integrin receptor antagonists having dibenzocycloheptene,dibenzocycloheptane and dibenzoxazepine scaffolds have been described inWO 97/01540, WO 98/30542, WO 99/11626, WO 99/15508, WO 00/33838, U.S.Pat. Nos. 6,008,213, and 6,069,158. Other osteoclast integrin receptorantagonists incorporating backbone conformational ring constraints havebeen described in the patent literature. Published patent applicationsor issued patents disclosing antagonists having a phenyl constraintinclude WO 98/00395, WO 99/32457, WO 99/37621, WO 99/44994, WO 99/45927,WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, EP 0 820,988, EP 0820,991, U.S. Pat. Nos. 5,741,796; 5,773,644; 5,773,646; 5,843,906;5,852,210; 5,929,120; 5,952,381; 6,028,223; and 6,040,311. Publishedpatent applications or issued patents disclosing antagonists having amonocyclic ring constraint include WO 99/26945, WO 99/30709, WO99/30713, WO 99/31099, WO 99/59992, WO 00/00486, WO 00/09503, EP 0796,855, EP 0 928,790, EP 0 928,793, U.S. Pat. Nos. 5,710,159;5,723,480; 5,981,546; 6,017,926; and 6,066,648. Published patentapplications or issued patents disclosing antagonists having a bicyclicring constraint include WO 98/23608, WO 98/35949, WO 99/33798, EP 0853,084, U.S. Pat. Nos. 5,760,028; 5,919,792; and 5,925,655. Referenceis also made to the following reviews for additional scientific andpatent literature that concern alpha v integrin antagonists: M. E.Duggan, et al., “Ligands to the integrin receptor αvβ3, Exp. Opin. Ther.Patents, 10: 1367-1383 (2000); M. Gowen, et al., “Emerging therapies forosteoporosis,” Emerging Drugs, 5: 1-43 (2000); J. S. Kerr, et al.,“Small molecule αv integrin antagonists: novel anticancer agents,” Exp.Opin. Invest. Drugs, 9: 1271-1291 (2000); and W. H. Miller, et al.,“Identification and in vivo efficacy of small-molecule antagonists ofintegrin αvβ3 (the vitronectin receptor),” Drug Discovers Today, 5:397-408 (2000).

[0292] Cathepsin K, formerly known as cathepsin O2, is a cysteineprotease published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

[0293] Members of the class of HMG-CoA reductase inhibitors, known asthe “statins,” have been found to trigger the growth of new bone,replacing bone mass lost as a result of osteoporosis (see The WallStreet Journal, Friday, Dec. 3, 1999, page B1). Therefore, the statinshold promise for the treatment of bone resorption. Examples of HMG-CoAreductase inhibitors include statins in their lactonized or dihydroxyopen acid forms and pharmaceutically acceptable salts and estersthereof, including but not limited to lovastatin (see U.S. Pat. No.4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin, particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin,also known as ZD-4522 (see U.S. Pat. No. 5,260,440) and pitavastatin,also referred to as NK-104, itavastatin, or nisvastatin (see PCTinternational application publication number WO 97/23200).

[0294] Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, may also be employed together with the tissue selectiveandrogen receptor modulators of structural formula I. The proton ATPasewhich is found on the apical membrane of the osteoclast has beenreported to play a significant role in the bone resorption process.Therefore, this proton pump represents an attractive target for thedesign of inhibitors of bone resorption which are potentially useful forthe treatment and prevention of osteoporosis and related metabolicdiseases [see C. Farina et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone antiresorptive agents,” DDT, 4:163-172 (1999)].

[0295] The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts [see M. Nakagawa et al.,“Vascular endothelial growth factor (VEGF) directly enhancesosteoclastic bone resorption and survival of mature osteoclasts,” FEBSLetters, 473: 161-164 (2000)]. Therefore, the development of antagonistsof VEGF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1,may provide yet a further approach to the treatment or prevention ofbone resorption.

[0296] Activators of the peroxisome proliferator-activated receptor-γ(PPARγ), such as the thiazolidinediones (TZD's), inhibit osteoclast-likecell formation and bone resorption in vitro. Results reported by R.Okazaki et al. in Endocrinolog, 140: 5060-5065 (1999) point to a localmechanism on bone marrow cells as well as a systemic one on glucosemetabolism. Nonlimiting examples of PPARγ activators include theglitazones, such as troglitazone, pioglitazone, rosiglitazone, and BRL49653.

[0297] Calcitonin may also be employed together with the tissueselective androgen receptor modulator of structural formula I.Calcitonin is preferentially employed as salmon nasal spray (Azra etal., Calcitonin. 1996. In: J. P. Bilezikian, et al., Ed., Principles ofBone Biology, San Diego: Academic Press; and Silverman, “Calcitonin,”Rheumatic Disease Clinics of North America, 27: 187-196, 2001)

[0298] Protein kinase inhibitors may also be employed together with thetissue selective androgen receptor modulators of structural formula I.Kinase inhibitors include those disclosed in WO 01/17562 and are in oneembodiment selected from inhibitors of P-38. Specific embodiments ofP-38 inhibitors useful in the present invention include SB 203580[Badger et al., “Pharmacological profile of SB 203580, a selectiveinhibitor of cytokine suppressive binding protein/p38 kinase, in animalmodels of arthritis, bone resorption, endotoxin shock, and immunefunction,” J. Pharmacol. Exp. Ther., 279: 1453-1461 (1996)].

[0299] Osteoanabolic agents are those agents that are known in the artto build bone by increasing the production of the bone protein matrix.Such osteoanabolic agents include, for example, the various forms ofparathyroid hormone (PTH) such as naturally occurring PTH (1-84), PTH(1-34), analogs thereof, native or with substitutions and particularlyparathyroid hormone subcutaneous injection. PTH has been found toincrease the activity of osteoblasts, the cells that form bone, therebypromoting the synthesis of new bone (Modern Drug Discovery, Vol. 3, No.8, 2000). In studies reported at the First World Congress onOsteoporosis held in Chicago in June 2000, women in combinedPTH-estrogen therapy exhibited a 12.8% increase in spinal bone mass anda 4.4% increase in total hip mass. Another study presented at the samemeeting showed that PTH could increase bone size as well as density. Aclinical trial of the effect of the human parathyroid hormone 1-34fragment [hPTH(1-34)] on postmenopausal osteoporotic women resulted in≧65% reduction in spine fractures and a 54% reduction in nonvertebralfractures, after a median of 22 months of treatment [see J. M. Hock,Bone, 27: 467-469 (2000) and S. Mohan, et al., Bone, 27: 471-478 (2000),and references cited therein]. Thus, PTH and fragments thereof, such ashPTH(1-34), may prove to be efficacious in the treatment of osteoporosisalone or in combination with other agents, such as the tissue selectiveandrogen receptor modulators of the present invention. An injectablerecombinant form of human PTH, Forteo (teriparatide), has receivedregulatory approval in the U.S. for the treatment of osteoporosis.

[0300] Also useful in combination with the SARMs of the presentinvention are calcium receptor antagonists which induce the secretion ofPTH as described by Gowen et al., in “Antagonizing the parathyroidcalcium receptor stimulates parathyroid hormone secretion and boneformation in osteopenic rats,” J. Clin. Invest. 105: 1595-604 (2000).

[0301] Growth hormone secretagogues, growth hormone, growth hormonereleasing hormone and the like are also osteoanabolic agents which maybe employed with the compounds according to structural formula I for thetreatment of osteoporosis. Representative growth hormone secretagoguesare disclosed in U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S.Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241;U.S. Pat. No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No.5,317,017; U.S. Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat.No. 5,434,261; U.S. Pat. No. 5,438,136; U.S. Pat. No. 5,494,919; U.S.Pat. No. 5,494,920; U.S. Pat. No. 5,492,916; U.S. Pat. No. 5,536,716;EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT PatentPub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub.No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO94/19367; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO95/34311; PCT Patent Pub. No. WO 96/02530; Science, 260, 1640-1643 (Jun.11, 1993); Ann. Rep. Med. Chem., 28: 177-186 (1993); Bioorg. Med. Chem.Lett., 4: 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA, 92:7001-7005 (1995).

[0302] Insulin-like growth factor (IGF) may also be employed togetherwith the tissue selective androgen receptor modulators of structuralformula I. Insulin-like growth factors may be selected from Insulin-likeGrowth Factor I, alone or in combination with IGF binding protein 3 andIGF II [See Johannson and Rosen, “The IGFs as potential therapy formetabolic bone diseases,” 1996, In: Bilezikian, et al., Ed., Principlesof Bone Biology, San Diego: Academic Press; and Ghiron et al., “Effectsof recombinant insulin-like growth factor-I and growth hormone on boneturnover in elderly women,” J. Bone Miner. Res. 10: 1844-1852 (1995)].

[0303] Bone morphogenetic protein (BMP) may also be employed togetherwith the tissue selective androgen receptor modulators of structuralformula I. Bone morphogenetic protein includes BMP 2, 3, 5, 6, 7, aswell as related molecules TGF beta and GDF 5 [Rosen et al., “Bonemorphogenetic proteins,” 1996. In: J. P. Bilezikian, et al., Ed.,Principles of Bone Biology, San Diego: Academic Press; and Wang E A,“Bone morphogenetic proteins (BMPs): therapeutic potential in healingbony defects,” Trends Biotechnol., 11: 379-383 (1993)].

[0304] Inhibitors of BMP antagonism may also be employed together withthe tissue selective androgen receptor modulators of structural formulaI. BMP antagonist inhibitors are in one embodiment selected frominhibitors of the BMP antagonists SOST, noggin, chordin, gremlin, anddan [Massague and Chen, “Controlling TGF-beta signaling,” Genes Dev.,14: 627-644, 2000; Aspenberg et al., “The bone morphogenetic proteinsantagonist Noggin inhibits membranous ossification,” J. Bone Miner. Res.16: 497-500, 2001; Brunkow et al., “Bone dysplasia sclerosteosis resultsfrom loss of the SOST gene product, a novel cystine knot-containingprotein,” Am. J. Hum. Genet. 68: 577-89 (2001)].

[0305] The tissue-selective androgen receptor modulators of the presentinvention may also be combined with the polypeptide osteoprotegerin forthe treatment of conditions associated with bone loss, such asosteoporosis. Preferably osteoprotegerin is mammalian osteoprotegerinand more preferably human osteoprotegerin. The polypeptideosteoprotegerin, a member ot the tumor necrosis factor receptorsuperfamily, is useful to treat bone diseases characterized by increasedbone loss, such as osteoporosis. Reference is made to U.S. Pat. No.6,288,032, which is incorporated by reference herein in its entirety.

[0306] Prostaglandin derivatives may also be employed together with thetissue selective androgen receptor modulators of structural formula I.Prostaglandin derivatives are in one embodiment selected from agonistsof prostaglandin receptor EP1, EP2, EP4, FP and IP or a derivativethereof [Pilbeam et al., “Prostaglandins and bone metabolism,” 1996. In:Bilezikian, et al. Ed. Principles of Bone Biology, San Diego: AcademicPress; Weinreb et al., “Expression of the prostaglandin E(2) (PGE(2))receptor subtype EP(4) and its regulation by PGE(2) in osteoblastic celllines and adult rat bone tissue,” Bone, 28: 275-281 (2001)].

[0307] Fibroblast growth factors may also be employed together with thetissue selective androgen receptor modulators of structural formula I.Fibroblast growth factors include aFGF, bFGF and related peptides withFGF activity [Hurley Florkiewicz, “Fibroblast growth factor and vascularendothelial growth factor families,” 1996. In: J. P. Bilezikian, et al.,Ed. Principles of Bone Biology, San Diego: Academic Press].

[0308] In addition to bone resorption inhibitors and osteoanabolicagents, there are also other agents known to be beneficial for theskeleton through mechanisms which are not precisely defined. Theseagents may also be favorably combined with the tissue selective androgenreceptor modulators of structural formula I.

[0309] Vitamin D and vitamin D derivatives may also be employed togetherwith the tissue selective androgen receptor modulator of structuralformula I. Vitamin D and vitamin D derivatives include natural vitaminD, 25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3, 1α-OH-vitamin D3,1α-OH-vitamin D2, dihydrotachysterol, 26,27-F6-1α,25(OH)₂ vitamin D3,19-nor-1α,25(OH)₂ vitamin D3, 22-oxacalcitriol, calcipotriol,1α,25(OH)₂-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089,20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71, 1α,24(S)-(OH)₂ vitamin D3,1α,24(R)-(OH)₂ vitamin D3 [See, Jones G., “Pharmacological mechanisms oftherapeutics: vitamin D and analogs,” 1996. In: J. P. Bilezikian, et.al. Ed. Principles of Bone Biology, San Diego: Academic Press].

[0310] Vitamin K and vitamin K derivatives may also be employed togetherwith the tissue selective androgen receptor modulators of structuralformula I. Vitamin K and vitamin K derivatives include menatetrenone(vitamin K2) [see Shiraki et al., “Vitamin K2 (menatetrenone)effectively prevents fractures and sustains lumbar bone mineral densityin osteoporosis,” J. Bone Miner. Res., 15: 515-521 (2000)].

[0311] Soy isoflavones, including ipriflavone, may be employed togetherwith the tissue selective androgen receptor modulators of structuralformula I.

[0312] Fluoride salts, including sodium fluoride (NaF) and monosodiumfluorophosphate (MFP), may also be employed together with the tissueselective androgen receptor modulators of structural formula I, Dietarycalcium supplements may also be employed together with the tissueselective androgen receptor modulators of structural formula I. Dietarycalcium supplements include calcium carbonate, calcium citrate, andnatural calcium salts (Heaney. Calcium. 1996. In: J. P. Bilezikian, etal., Ed., Principles of Bone Biology, San Diego: Academic Press).

[0313] Daily dosage ranges for bone resorption inhibitors, osteoanabolicagents and other agents which may be used to benefit the skeleton whenused in combination with the compounds of structural formula I are thosewhich are known in the art. In such combinations, generally the dailydosage range for the tissue selective androgen receptor modulator ofstructural formula I is 0.01 to 1000 mg per adult human per day, morepreferably from 0.1 to 200 mg/day. However, adjustments to decrease thedose of each agent may be made due to the increased efficacy of thecombined agent.

[0314] In particular, when a bisphosphonate is employed, dosages of 2.5to 100 mg/day (measured as the free bisphosphonic acid) are appropriatefor treatment, more preferably 5 to 20 mg/day, especially about 10mg/day. Prophylactically, doses of about 2.5 to about 10 mg/day andespecially about 5 mg/day should be employed. For reduction inside-effects, it may be desirable to administer the combination of thecompound of structural formula I and the bisphosphonate once a week. Foronce weekly administration, doses of about 15 mg to 700 mg per week ofbisphosphonate and 0.07 to 7000 mg of the compound of structural formulaI may be employed, either separately, or in a combined dosage form. Thecompound of structural formula I may be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

[0315] For the treatment of atherosclerosis, hypercholesterolemia, andhyperlipidemia, the compounds of structural formula I may be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be lipid-altering compoundssuch as HMG-CoA reductase inhibitors, or agents having otherpharmaceutical activities, or agents that have both lipid-alteringeffects and other pharmaceutical activities. Examples of HMG-CoAreductase inhibitors include statins in their lactonized or dihydroxyopen acid forms and pharmaceutically acceptable salts and estersthereof, including but not limited to lovastatin (see U.S. Pat. No.4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the amnmonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin, particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatin,also referred to as NK-104 (see PCT international applicationpublication number WO 97/23200). Additional active agents which may beemployed in combination with a compound of structural formula I include,but are not limited to, HMG-CoA synthase inhibitors; squalene epoxidaseinhibitors; squalene synthetase inhibitors (also known as squalenesynthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase(ACAT) inhibitors including selective inhibitors of ACAT-1 or ACAT-2 aswell as dual inhibitors of ACAT-1 and -2; microsomal triglyceridetransfer protein (MTP) inhibitors; probucol; niacin; cholesterolabsorption inhibitors, such as SCH-58235, also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]4(S)-(4-hydroxyphenyl)-2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPARγ) agonists, including the compoundscommonly referred to as glitazones, for example troglitazone,pioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidinediones as well as thosePPARγ agonists outside the thiazohdinedione structural class; PPARαagonists, such as clofibrate, fenofibrate including micronizedfenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (alsoknown as pyridoxine) and the pharmaceutically acceptable salts thereofsuch as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folicacid or a pharmaceutically acceptable salt or ester thereof such as thesodium salt and the methylglucamine salt; anti-oxidant vitamins such asvitamin C and E and beta carotene; beta-blockers; angiotensin IIantagonists such as losartan; angiotensin converting enzyme inhibitors,such as enalapril and captopril; calcium channel blockers, such asnifedipine and diltiazem; endothelin antagonists; agents such as LXRligands that enhance ABC1 gene expression; bisphosphonate compounds,such as alendronate sodium; and cyclooxygenase-2 inhibitors, such asrofecoxib and celecoxib, as well as other agents known to be useful inthe treatment of these conditions.

[0316] Daily dosage ranges for HMG-CoA reductase inhibitors when used incombination with the compounds of structural formula I correspond tothose which are known in the art. Similarly, daily dosage ranges for theHMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; cholesterol absorption inhibitorsincluding ezetimibe; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors,including glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamnma (PPARγ)agonists; PPARα agonists; PPAR dual α/γ agonists; vitamin B₆; vitaminB₁₂; folic acid; anti-oxidant vitamins; beta-blockers; angiotensin IIantagonists; angiotensin converting enzyme inhibitors; calcium channelblockers; endothelin antagonists; agents such as LXR ligands thatenhance ABC1 gene expression; bisphosphonate compounds; andcyclooxygenase-2 inhibitors also correspond to those which are known inthe art, although due to the combined action with the compounds ofstructural formula I, the dosage may be somewhat lower when administeredin combination.

[0317] In accordance with the method of the present invention, theindividual components of the combination can be administered separatelyat different times during the course of therapy or concurrently individed or single combination forms. The instant invention is thereforeto be understood as embracing all such regimes of simultaneous oralternating treatment and the term “administering” is to be interpretedaccordingly. It will be understood that the scope of combinations of thecompounds of this invention with other agents useful for treatingdiseases caused by androgen deficiency or that can be ameliorated byaddition of androgen.

Preparation of the Compounds of the Invention

[0318] The compounds of structural formula I of the present inventioncan be prepared according to the procedures of the following Schemes andExamples, using appropriate materials and are further exemplified byspecific examples provided below.

[0319] Compounds of structural formula I can be prepared from a17β-carboxylic acid intermediate such as 1-1. Intermediate 1-1can beactivated such as by conversion into the corresponding acid chloride1-1by treatment with a halogenating agent in a suitable organic solvent,such as thionyl chloride or oxalyl chloride in the presence of DMF. Thederived acid chloride 1-1is then treated with an appropriatelysubstituted arylamine optionally in the presence of a suitable base suchas N-methylmorpholine and 4-(dimethylamino)-pyridine to afford thecompound of structural formula I, such as 1-1. Reference is made toHarrison and Harrison, Compendium of Organic Synthetic Methods, Volumes1-4, Wiley-Interscience, for a description of methods for the synthesisof carboxylic acid arylamides.

[0320] The preparation of 3-oxoandrost-4-ene-17β-carbonyl chloride (1-2)is described in U.S. Pat. No. 4,377,584, which is incorporated byreference herein in its entirety.

[0321] The following examples are provided to further illustrate detailsfor the preparation and use of the compounds of the present invention.They are not intended to be limitations on the scope of the instantinvention in any way, and they should not be so construed. Furthermore,the compounds described in the following examples are not to beconstrued as forming the only genus that is considered as the invention,and any combination of the compounds or their moieties may itself form agenus. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. All temperatures arein degrees Celsius unless noted otherwise.

EXAMPLE 1

[0322]

[0323] Step A: 3-oxoandrost-4-ene-17β-carbonyl chloride (1-2)

[0324] To a solution of 3-oxoandrost-4-ene-17-beta-carboxylic acid (1-1)(1.0 g, 3.16 mmol) in 15.8 mL anhydrous CH₂Cl₂ at 0° C. under a nitrogenatmosphere was added 0.010 mL DMF followed by slow addition of oxalylchloride (0.330 mL, 3.78 mmol). The ice bath was then removed and thereaction was stirred at room temperature for several hours. The mixturewas concentrated to a tan foam which was then dissolved in 10.0 mL ofanhydrous CH₂Cl₂, stored in the freezer, and used as it is in subsequentreactions.

[0325] Step B:(17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(1-3a)

[0326] To a solution of N-methylmorpholine (0.28 g, 2.8 mmol) and2-(trifluoromethyl)aniline (0.5 g, 3.1 mmol) in anhydrous CH₂Cl₂ (3.0mL) at 0° C. under a nitrogen atmosphere was added a solution of3-oxoandrost-4-ene-17β-carbonyl chloride from Step A (2.56 mmol) inanhydrous CH₂Cl₂ (8.1 mL) dropwise. The ice bath was removed and themixture stirred at room temperature overnight. The reaction was thenconcentrated and the residue was purified by flash chromatography onsilica gel eluting with 0 to 50% EtOAc-hexanes to afford the desiredproduct as a white solid.

[0327]¹H-NMR (CDCl₃): δ 8.32 (d, J=8.3 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H),7.55 (t, J=7.9 Hz, 1H), 7.40 (s, 1H), 7.20 (t, J=7.6 Hz, 1H), 5.75 (s,1H), 2.47-2.26 (m, 5H), 2.12 (dt, J=12.0, 3.2 Hz, 1H), 2.04 (m, 1H),1.90 (m, 2H), 1.82-1.57 (m, 4H), 1.53-1.34 (m, 3H), 1.20 (m, 4H),1.13-0.97 (m, 2H), 0.82 (s, 3H).

[0328] Mass spectrum: (M⁺+H) 460.2487.

[0329] Following procedures similar to that described above for Example1, the following compounds were prepared:

Parent Ion m/z Ex. # X (M + H) 2 3-CF₃ 460 3 4-CF₃ 460 4 2-OMe 422 53-OMe 422 6 4-OMe 422 7 —H 392 8 2-Cl 426 9 3-Cl 426 10 4-Cl 426 11 2-Me406 12 3-Me 406 13 4-Me 406 14 2-F 410 15 3-F 410 16 4-F 410 17 2-Br 47018 2-I 518 19 3-OMe, 5-CF₃ 490

[0330]

EXAMPLE 20(17β)-N-Methyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide(2-2)

[0331] To a suspension of NaH (0.009 g, 0.24 mmol) in 1.0 mL anhydrousTHF at 0° C. under N₂ was added(17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(2-1) (0.10 g, 0.22 mmol). The mixture was stirred for 30-45 min,followed by addition of methyl iodide (0.046 g, 0.33 mmol). The ice bathwas removed and the solution was stirred at room temperature for 45 min.The reaction was quenched with 10% aqueous KHSO₄ solution and extractedwith EtOAc. The organic phase was washed with saturated NaHCO₃ solutionand brine and dried with MgSO₄. After removal of the solvent, theresidue was purified by flash silica gel chromatography (0 to 50%EtOAc-hexanes) to give the desired product 2-2as a white solid.

[0332] MS (M⁺+H) found 474.2644; calc: 474.25.

EXAMPLE 21(17β)-6-Methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(3-4)

[0333] Step A:(17β)-6-(Hydroxymethyl)-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(3-2, 3-3)

[0334] To a suspension of(17β)-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(3-1) (4.13 g, 8.99 mmol) in 24 mL MeOH under N₂ was added pyrrolidine(1.34 g, 18.87 mmol). The mixture was heated to reflux for 15-20 min.The mixture was then cooled in an ice bath and filtered. The solid wasdissolved in a mixture of 70 mL EtOH and 35 mL benzene. 37% aqueousformaldehyde (3.48 mL, 46.7 mmol) was added. The yellowish solution wasstirred overnight. The reaction mixture was then concentrated andpurified by flash silica gel chromatography (0 to 100% EtOAc-hexane) toafford the 6-hydroxymethyl derivative as a mixture of α and β epimers(3-2 and 3-3).

[0335] Step B:(17β)-6-Methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(3-4)

[0336] A mixture of(17β)-6-(hydroxymethyl)-3-oxo-N-[4--(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(3-2 and 3-3) (0.57 g, 1.2 mmol) was dissolved in 15 mL 0.6N HCl indioxane and stirred at rt. After 3 hr, it was diluted with a largeexcess of dioxane and stirred overnight. After removal of the solvent,the residue was dissolved in CHCl₃ and washed with water, saturatedNaHCO₃ solution, and brine, then dried with MgSO₄ and concentrated. Theresidue was purified by flash silica gel chromatography (0 to 50%EtOAc/hexane) to afford 3-4 as the desired product.

[0337]¹H-NMR (CDCl₃) δ 7.66 (d, 2H), 7.58 (d, 2H), 7.18 (s, 1H), 5.93(s, 1H), 5.08 (s, 1H), 4.97 (s, 1H), 2.52-2.31 (m, 5H), 2.07 (m, 2H),1.93-1.67 (m, 6H), 1.53-1.39 (m, 3H), 1.28-1.13 (m, 2H), 1.11 (s, 3H),0.80 (s, 3H).

EXAMPLE 22(17β)-6,6-Ethyleno-3-oxo-N-(4-trifluoromethylpheny)-androst-4-ene-17-carboxamide(3-5)

[0338] To a suspension of NaH (0.06 g, 1.4 mmol) in 1.0 mL sieve-driedDMSO at room temperature under N₂ was added trimethylsulfoxonium iodide(0.34 g, 1.5 mmol). The mixture was stirred for 1.5 hr. before asolution of(17β)-6-methylene-3-oxo-N-[4(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(3-4) (0.24 g, 0.5 mmol) in 3-4 mL DMSO was added dropwise. After 30min, the reaction was quenched with 10% KHSO₄ solution and extractedwith CHCl₃. The organic layer was washed with saturated NaHCO₃ solutionand brine, then dried with MgSO₄ and concentrated. The residue waspurification by preparative HPLC (C₁₈; 70% MeOH with 5 to 30%MeCN-water) to give the desired product 3-3as a white solid.

[0339]¹H-NMR (CDCl₃) δ 7.67 (d, 2H), 7.58 (d, 2H), 7.25 (s, 1H), 5.66(s, 1H), 2.37 (m, 4H), 2.05 (m, 2H), 1.85 (m, 2H), 1.70 (m, 3H), 1.55(m, 3H), 1.36 (m, 2H), 1.27 (s, 3H), 1.11 (m, 4H), 0.81 (m, 4H), 0.44(m, 2H).

[0340] MS (M⁺+H) 486.2567.

EXAMPLES 23 AND 24(17β)-6β-Ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(4-1) and(17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(4-2)

[0341] Step A:(17β)-6-ethyl-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-5-ene-17-carboxamide

[0342] To a solution of 3.0 M MeMgBr (0.36 mL, 1.09 mmol) in ether underN₂ was added 2.2 mL Argon-purged, anhydrous THF. The mixture was cooledto 0° C. CuCl (0.014 g, 0.14 mmol) was added, and the reaction wasstirred for 5 min before adding(17β)-6-methylene-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(3-4) (0.12 g, 0.25 mmol) as a solid. After several hours the reactionwas quenched by dropwise addition of 5.0 mL of Ar-purged water, thenpartitioned between CHCl₃ and 10% KHSO₄ solution. The organic phase waswashed with saturated NaHCO₃ solution and brine, then dried with MgSO₄and concentrated. The residue was purified by flash silica gelchromatography (0 to 30% EtOAc/hexane) and concentrated to yield aclear, colorless oil, which was further purified by preparative HPLC(C₁₈; 70% MeOH with 5 to 30% MeCN-water) to provide the desired product.

[0343]¹H-NMR (CDCl₃) δ 7.66 (d, 2H), 7.58 (d, 2H), 7.18 (s, 1H), 3.31(dd, 1H), 3.04 (dt, 1H), 2.48 (m, 1H), 2.32 (m, 3H), 2.03 (m, 4H), 1.85(m, 3H), 1.71-1.49 (m, 5H), 1.40 (m, 2H), 1.28-1.05 (m, 5H), 0.91 (t,3H), 0.80 (s, 3H).

[0344] Step B:(17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(4-1) and(17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(4-2)

[0345] To a solution of(17β)-6-ethyl-3-oxo-N-[4-(trifluoromethyl)-phenyl]androst-5-ene-17-carboxamidefrom Step A (0.027 g, 0.055 mmol) in 1.0 mL THF was added 1.0 N HClsolution (0.5 mL). After 2 hr, the reaction mixture was concentrated.The residue was purified by preparative HPLC (C₁₈; 70% MeOH with 5 to30% MeCN-water) to yield to afford the resolved 6-position isomers:

[0346] 6-alpha isomer (4-2): ¹H-NMR (CDCl₃) δ 7.68 (d, 2H), 7.57 (d,2H), 7.30 (s, 1H), 5.80 (s, 1H), 2.45-2.29 (m, 4H), 2.18 (m, 1H), 2.02(m, 3H), 1.90-1.61 (m, 6H) 1.52-1.23 (m, 5H), 1.19 (s, 3H), 1.16 (m,1H), 1.02 (dt, 1H), 0.95 (t, 3H), 0.81 (s, 3H), 0.74 (q, 1H).

[0347] 6-beta isomer (4-1): ¹H-NMR (CDCl₃) δ 7.65 (d, 2H), 7.58 (d, 2H),7.10 (s, 1H), 5.74 (s, 1H), 2.54-2.28 (m, 5H), 2.05 (m, 2H), 1.97-1.15(m), 1.02 (m, 2H), 0.89 (t, 3H), 0.82 (s, 3H).

EXAMPLE 25(17β)-7-Methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide(5-3)

[0348] Step A:(17β)-3-oxo-N-[2-(trifluoromethyl)phenyl]androsta-4,6-diene-17-carboxamide(5-2)

[0349] A mixture of(17β)-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(2-1) (3.74 g, 8.14 mmol) and p-chloranil (2.40 g, 9.77 mmol) int-butanol (40 mL) under N₂ was heated to reflux for 90 min. The reactionwas concentrated and the residue dissolved in EtOAc and washed with 0.5N NaOH solution (2×60 mL), 10% KHSO₄ solution, and brine. Upon removalof the solvent, the residue was purified by flash chromatography onsilica gel (0 to 35% EtOAc-hexanes) to afford 5-2 as a brownish foam.

[0350] MS (M⁺+H) 457.8.

[0351] Step B:(17β)-7-methyl-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-5-ene-17-carboxamide(5-3)

[0352] To a solution of 3.0 M methylmagnesium bromide (2.35 mmol) inether under a stream of N₂ was added 6.0 mL degassed THF. The solutionwas cooled to 0° C., then CuCl (0.03 g, 0.300 mmol) was added. Themixture was stirred for 5 min. A solution of the compound from Step A(5-2) (0.25 g, 0.55 mmol) in 6.0 mL degassed THF was added. The reactionwas warmed to room temperature overnight. It was quenched by slowaddition of 2.0 mL degassed water, then diluted with 10% KHSO₄ solutionand EtOAc. The organic phase was washed with 10% KHSO₄ solution,saturated NaHCO₃ solution, and brine. After removal of the solvent, theresidue was purified by preparative HPLC (C₁₈; 70% MeOH with 5 to 30%MeCN-water) to provide 5-5.

[0353] MS (M⁺+H) 474.3.

[0354] Step C:(17β)-7-methyl-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide(5-4)

[0355] A solution of the compound from Step B (5-3) (0.057 g, 0.12mmol), dioxane (0.5 mL) and 1.0 N HCl solution (0.5 mL) was heated to50° C. for 2 hr. The reaction was then concentrated to yield the desiredproduct as an 8:1 mixture of epimers at C-7.

[0356] MS (M⁺+H) 474.3.

EXAMPLES 26 AND 27(1aR,5aR,7aS,8S,10cR)-5a,7a-Dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide(6-1) and (1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide(6-2)

[0357] To a suspension of NaH (0.25 g, 6.18 mmol) in 7.4 mL DMSO (driedover molecular sieves) at room temperature under N₂ was addedtrimethylsulfoxonium iodide (1.50 g, 6.85 mmol). The mixture was stirredfor 1.5 hr. A solution of(17β)-3-oxo-N-[2-(trifluoromethyl)phenyl]androsta-4,6-diene-17-carboxamide(5-1) (0.68 g, 1.49 mmol) in 10 mL DMSO was added slowly. The solutionwas stirred at room temperature overnight. The reaction was thenquenched by dropwise addition of 10% KHSO₄ solution and extracted withCHCl₃. The organic phase was washed with 10% KHSO₄ solution, saturatedNaHCO₃ solution, and brine, then dried with MgSO₄. After removal of thesolvent, the residue was purified by chiral preparative HPLC (ChiralpakAD, 85% Hexanes (0.1% diethylamine); 15% 2-propanol) to yield thedesired resolved products 6-6and 6-2.

[0358] 6-6: (1aR,5aR,7aS,8S,10cR)-5a,7a-Dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide

[0359] MS (M⁺+H) 472.2443.

[0360] 6-6: (1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide

[0361] MS (M⁺+H) 472.2423.

EXAMPLE 28 Oral Composition

[0362] As a specific embodiment of an oral composition of a compound ofthis invention, 50 mg of a compound of the present invention isformatted with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

EXAMPLE 29 Transdermal Patch Formulation

[0363] Ingredient Amount Compound of formula I 40 g Silicone fluid 45 gColloidal silicone dioxide 2.5 g 

[0364] The silicone fluid and compound of structural formula I are mixedtogether and the colloidal silicone dioxide is added to increaseviscosity. The material is then dosed into a subsequently heat sealedpolymeric laminate comprised of the following: polyester release liner,skin contact adhesive composed of silicone or acrylic polymers, acontrol membrane which is a polyolefin (e.g. polyethylene, polyvinylacetate or polyurethane), and an impermeable backing membrane made of apolyester multilaminate. The resulting laminated sheet is then cut into10 cm² patches. For 100 Patches.

EXAMPLE 30 Suppository

[0365] Ingredient Amount Compound of structural formula I  25 gPolyethylene glycol 1000 1481 g  Polyethylene glycol 4000 494 g

[0366] The polyethylene glycol 1000 and polyethylene glycol 4000 aremixed and melted. The compound of structural formula I is mixed into themolten mixture, poured into molds and allowed to cool. For 1000suppositories.

EXAMPLE 31 Injectable Solution

[0367] Ingredient Amount Compound of structural formula I 5 g Bufferingagents q.s. Propylene glycol 400 mg Water for injection 600 mL

[0368] The compound of structural formula I and buffering agents aredissolved in the propylene glycol at about 50° C. The water forinjection is then added with stirring and the resulting solution isfiltered, filled into ampules, sealed and sterilized by autoclaving. For1000 Ampules.

EXAMPLE 32 Injectable Solution

[0369] Ingredient Amount Compound of structural formula I 5 g Bufferingagents q.s. Magnesium sulfate heptahydrate 100 mg Water for injection880 mL

[0370] The compound of structural formula I, magnesium sulfateheptahydrate and buffering agents are dissolved in the water forinjection with stirring, and the resulting solution is filtered, filledinto ampoules, sealed and sterilized by autoclaving. For 1000 Ampoules.

[0371] The following assays were used to characterize the activity ofthe tissue selective androgen receptor modulators of the presentinvention.

In vitro and in vivo Assays for Identification of Compounds with SarmActivity

[0372] 1. Hydroxylapatite-based Radioligand Displacement Assay ofCompound Affinity for Endogenously Expressed AR

[0373] Materials:

[0374] Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1mM beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)

[0375] 50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mMTris, pH 8.0 and 1 mM EDTA.

[0376] Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mMEGTA. 95% EtOH

[0377] Methyltrienolone, [17α-methyl-³H], (R1881*); NEN NET590

[0378] Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)

[0379] Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453

[0380] Hydroxylapatite Fast Flow; Calbiochem Cat#391947

[0381] Molybdate=Molybdic Acid (Sigma, M1651)

[0382] MDA-MB-453 Cell Culture Media: RPMI 1640 (Gibco 11835-055) w/23.8mM NaHCO₃, 2 mM L-glutamine In 500 mL of complete media Final conc. 10mL (1 M Hepes) 20 mM 5 mL (200 mM L-glu)  4 mM 0.5 mL (10 mg/mL humaninsulin) 10 μg/mL in 0.01 N HCl Calbiochem#407694-S) 50 mL FBS (SigmaF2442) 10% 1 mL (10 mg/mL Gentamicin 20 μg/mL Gibco#15710-072)

[0383] Cell Passaging:

[0384] Cells (Hall R. E., et al., European Journal of Cancer, 30A:484-490 (1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA isdiluted in the same PBS 1:10. The cell layers are rinsed with 1×Trypsin, extra Trypsin is poured out, and the cell layers are incubatedat 37° C. for 2 min. The flask is tapped and checked for signs of celldetachment. Once the cells begin to slide off the flask, the completemedia is added to kill the trypsin. The cells are counted at this point,then diluted to the appropriate concentration and split into flasks ordishes for further culturing (Usually 1:3 to 1:6 dilution).

[0385] Preparation of MDA-MB-453 Cell Lysate

[0386] When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 min at4° C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mMEDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate,pH 7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid nitrogen or ethanol/dry ice bath and transferred to −80° C.freezer on dry ice. Before setting up the binding assay, the frozensamples are left on ice-water to just thaw (˜1 hr). Then the samples arecentrifuged at 12,500 g to 20,000 g for 30 min at 4° C. The supernatantis used to set-up assay right away. If using 50 μL of supernatant, thetest compound can be prepared in 50 μL of the TEGM buffer.

[0387] Procedure for Multiple Compound Screening:

[0388] 1× TEGM buffer is prepared, and the isotope-containing assaymixture is prepared in the following order: EtOH (2% final concentrationin reaction), ³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and 1×TEGM. [eg. For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10³H-R1881 stock+2300 μL (100×23) 1× TEGM]. The compound is seriallydiluted, e.g., if starting final conc. is 1 μM, and the compound is in25 μL of solution, for duplicate samples, 75μL of 4×1 μM solution ismade and 3 μL of 100 μM is added to 72 μL of buffer, and 1:5 serialdilution.

[0389] 25 μL of ³H-R1881 trace and 25 μL compound solution are firstmixed together, followed by addition of 50 μL receptor solution. Thereaction is gently mixed, spun briefly at about 200 rpm and incubated at4° C. overnight. 100 μL of 50% HAP slurry is prepared and added to theincubated reaction which is then vortexed and incubated on ice for 5 to10 minutes. The reaction mixture is vortexed twice more to resuspend HAPwhile incubating reaction. The samples in 96-well format are then washedin wash buffer using The FilterMate™ Universal Harvester plate washer(Packard). The washing process transfers HAP pellet containingligand-bound expressed receptor to Unifilter-96 GF/B filter plate(Packard). The HAP pellet on the filter plate is incubated with 50 μL ofMICROSCINT (Packard) scintillint for 30 minutes before being counted onthe TopCount microscintillation counter (Packard). IC₅₀s are calculatedusing R1881 as a reference. Tissue selective androgen receptormodulators of the present invention displayed IC₅₀ values of 1micromolar or less.

[0390] 2. MMP1 Promoter Suppression, Transient Transfection Assay(TRAMPS)

[0391] HepG2 cells are cultured in phenol red free MEM containing 10%charcoal-treated FCS at 37C with 5% CO₂. For transfection, cells areplated at 10,000 cells/well in 96 well white, clear bottom plates.Twenty four hours later, cells are co-transfected with a MMP1promoter-luciferase reporter construct and a rhesus monkey expressionconstruct (50:1 ratio) using FuGENE6 transfection reagent, following theprotocol recommended by manufacturer. The MMP1 promoter-luciferasereporter construct is generated by insertion of a human MMP1 promoterfragment (−179/+63) into pGL2 luciferase reporter construct (Promega)and a rhesus monkey AR expression construct is generated in a CMV-Tag2Bexpression vector (Stratagene). Cells are further cultured for 24 hoursand then treated with test compounds in the presence of 100 nMphorbol-12-myristate-13-acetate (PMA), used to increase the basalactivity of MMP1 promoter. The compounds are added at this point, at arange of 1000 nM to 0.03 nM, 10 dilutions, at a concentration on 10×,{fraction (1/10)} th volume (example:10 microliters of ligand at 10×added to 100 microliters of media already in the well). Cells arefurther cultured for an additional 48 hours. Cells are then washed twicewith PBS and lysed by adding 70 μL of Lysis Buffer (1×, Promega) to thewells. The luciferase activity is measured in a 96-well format using a1450 Microbeta Jet (Perkin Elmer) luminometer. Activity of testcompounds is presented as suppression of luciferase signal from thePMA-stimulated control levels. EC₅₀ and Emax values are reported. Tissueselective androgen receptor modulators of the present invention activaterepression typically with submicromolar EC₅₀ values and Emax valuesgreater than about 50%.

[0392] References:

[0393] a. Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A,“Fibroblast growth factor receptor signaling activates the humaninterstitial collagenase promoter via the bipartite Ets-AP1 element,”Mol. Endocrinol.11: 1129-44 (1997).

[0394] b. Schneikert J, Peterziel H, Defossez P A, Klocker H, Launoit Y,Cato A C, “Androgen receptor-Ets protein interaction is a novelmechanism for steroid hormone-mediated down-modulation of matrixmetalloproteinase expression,” J. Biol. Chem. 271: 23907-23913 (1996).

[0395] 3. A Mammalian Two-Hybrid Assay for the Ligand-inducedInteraction of N-Terminus and C-Terminus Domains of the AndrogenReceptor (Agonist Mode)

[0396] This assay assesses the ability of AR agonists to induce theinteraction between the N-terminal domain (NTD) and C-terminal domain(CTD) of rhAR that reflects the in vivo virilizing potential mediated byactivated androgen receptors. The interaction of NTD and CTD of rhAR isquantified as ligand induced association between a Gal4DBD-rhARCTDfusion protein and a VP16-rhARNTD fusion protein as a mammaliantwo-hybrid assay in CV-1 monkey kidney cells.

[0397] The day before transfection, CV-1 cells are trypsinized andcounted, and then plated at 20,000 cells/well in 96-well plates orlarger plates (scaled up accordingly) in DMEM+10% FCS. The next morning,CV-1 cells are cotransfected with pCBB1 (Gal4DBD-rhARLBD fusionconstruct expressed under the SV40 early promoter), pCBB2 (VP16-rhAR NTDfusion construct expressed under the SV40 early promoter) and pFR (Gal4responsive luciferase reporter, Promega) using LIPOFECTAMINE PLUSreagent (GIBCO-BRL) following the procedure recommended by the vendor.Briefly, DNA admixture of 0.05 μg pCBB1, 0.05 μg pCBB2 and 0.1 μg of pFRis mixed in 3.4 μL OPTI-MEM (GIBCO-BRL) mixed with “PLUS Reagent” (1.6μL, GIBCO-BRL) and incubated at room temperature (RT) for 15 min to formthe pre-complexed DNA.

[0398] For each well, 0.4 μL LIPOFECTAMINE Reagent (GBCO-BRL) is dilutedinto 4.6 μL OPTI-MEM in a second tube and mixed to form the dilutedLIPOFECTAMINE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15min at RT. The medium on the cells is replaced with 40 μL /wellOPTI-MEM, and 10 μL DNA-lipid complexes are added to each well. Thecomplexes are mixed into the medium gently and incubated at 37° C. at 5%CO₂ for 5 h. Following incubation, 200 μL /well D-MEM and 13%charcoal-stripped FCS are added, followed by incubation at 37° C. at 5%CO₂. After 24 hours, the test compounds are added at the desiredconcentration(s) (1 nM-10 μM). Forty eight hours later, luciferaseactivity is measured using LUC-Screen system (TROPIX) following themanufacturer's protocol. The assay is conducted directly in the wells bysequential addition of 50 μL each of assay solution 1 followed by assaysolution 2. After incubation for 40 minutes at room temperature,luminescence is directly measured with 2-5 second integration.

[0399] Activity of test compounds is calculated as the E_(max) relativeto the activity obtained with 3 nM R1881. Typical tissue-selectiveandrogen receptor modulators of the present invention display weak or noagonist activity in this assay with less than 50% agonist activity at 10micromolar.

[0400] Reference:

[0401] He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M,“Activation function in the human androgen receptor ligand bindingdomain mediates inter-domain communication with the NH(2)-terminaldomain,” J. Biol. Chem. 274: 37219-37225 (1999).

[0402] 4. A Mammalian Two-Hybrid Assay For Inhibition of Interactionbetween N-Terminus and C-Terminus Domains of Androgen Receptor(Antagonist Mode)

[0403] This assay assesses the ability of test compounds to antagonizethe stimulatory effects of R1881 on the interaction between NTD and CTDof rhAR in a mammalian two-hybrid assay in CV-1 cells as describedabove.

[0404] Forty eight hours after transfection, CV-1 cells are treated withtest compounds, typically at 10 μM, 3.3 μM, 1 μM, 0.33 μM, 100 nM, 33nM, 10 nM, 3.3 nM and 1 nM final concentrations. After incubation at 37°C. at 5% CO₂ for 10 -30 minutes, an AR agonist methyltrienolone (R1881)is added to a final concentration of 0.3 nM and incubated at 37° C.Forty-eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the protocol recommended by themanufacturer. The ability of test compounds to antagonize the action ofR1881 is calculated as the relative luminescence compared to the valuewith 0.3 nM R1881 alone.

[0405] SARM compounds of the present invention typically displayedantagonist activity in the present assay with IC₅₀ values less than 1micromolar.

[0406] 5. Trans-Activation Modulation of Androgen Receptor (TAMAR)

[0407] This assay assesses the ability of test compounds to controltranscription from the MMTV-LUC reporter gene in MDA-MB-453 cells, ahuman breast cancer cell line that naturally expresses the human AR. Theassay measures induction of a modified MMTV LTR/promoter linked to theLUC reporter gene.

[0408] 20,000 to 30,000 cells/well are plated in a white, clear-bottom96-well plate in “Exponential Growth Medium” which consists of phenolred-free RPMI 1640 containing 10% FBS, 4 mM L-glutamine, 20 mM HEPES, 10ug/mL human insulin, and 20 ug/mL gentamicin. Incubator conditions are37° C. and 5% CO₂. The transfection is done in batch mode. The cells aretrypsinized and counted to the right cell number in the proper amount offresh media, and then gently mixed with the Fugene/DNA cocktail mix andplated onto the 96-well plate. All the wells receive 200 μl ofmedium+lipid/DNA complex and are then incubated at 37° C. overnight. Thetransfection cocktail consists of serum-free Optimem, Fugene6 reagentand DNA. The manufacturer's (Roche Biochemical) protocol for cocktailsetup is followed. The lipid (μl) to DNA (μg) ratio is approximately 3:2and the incubation time is 20 min at room temperature. Sixteen to 24 hrsafter transfection, the cells are treated with test compounds such thatthe final DMSO (vehicle) concentration is <3%. The cells are exposed tothe test compounds for 48 hrs. After 48 hrs, the cells are lysed by aPromega cell culture lysis buffer for 30-60 min and then the luciferaseactivity in the extracts is assayed in the 96-well format luminometer.

[0409] Activity of test compounds is calculated as the E_(max) relativeto the activity obtained with 100 nM R1881.

[0410] References:

[0411] a. R. E. Hall, et al., “MDA-MB-453, an androgen-responsive humanbreast carcinoma cell line with high androgen receptor expression,” Eur.J. Cancer, 30A: 484-490 (1994).

[0412] b. R. E. Hall, et al., “Regulation of androgen receptor geneexpression by steroids and retinoic acid in human breast-cancer cells,”Int. J. Cancer., 52: 778-784 (1992).

[0413] 6. In Vivo Prostate Assay

[0414] Male Sprague-Dawley rats aged 9-10 weeks, the earliest age ofsexual maturity, are used in prevention mode. The goal is to measure thedegree to which androgen-like compounds delay the rapid deterioration(˜−85%) of the ventral prostate gland and seminal vesicles that occursduring a seven day period after removal of the testes (orchiectomy[ORX]).

[0415] Rats are orchiectomized (ORX). Each rat is weighed, thenanesthetized by isoflurane gas that is maintained to effect. A 1.5 cmanteroposterior incision is made in the scrotum. The right testicle isexteriorized. The spermatic artery and vas deferens are ligated with 4.0silk 0.5 cm proximal to the testicle. The testicle is freed by one cutof a small surgical scissors distal to the ligation site. The tissuestump is returned to the scrotum. The same is repeated for the lefttesticle. When both stumps are returned to the scrotum, the scrotum andoverlying skin are sutured closed with 4.0 silk. For Sham-ORX, allprocedures excepting ligation and scissors cutting are completed. Therats fully recover consciousness and full mobility within 10-15 minutes.

[0416] A dose of test compound is administered subcutaneously or orallyto the rat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

[0417] Necropsy and Endpoints:

[0418] The rat is first weighed, then anesthetized in a CO₂ chamberuntil near death. Approximately 5 ml whole blood is obtained by cardiacpuncture. The rat is then examined for certain signs of death andcompleteness of ORX. Next, the ventral portion of the prostate gland islocated and blunt dissected free in a highly stylized fashion. Theventral prostate is blotted dry for 3-5 seconds and then weighed (VPW).Finally, the seminal vesicle is located and dissected free. The ventralseminal vesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

[0419] Primary data for this assay are the weights of the ventralprostate and seminal vesicle. Secondary data include serum LH(luteinizing hormone) and FSH (follicle stimulating hormone), andpossible serum markers of bone formation and virilization. Data areanalyzed by ANOVA plus Fisher PLSD post-hoc test to identify intergroupdifferences. The extent to which test compounds inhibit ORX-induced lossof VPW and SVWT is assessed.

[0420] 7. In Vivo Bone Formation Assay:

[0421] Female Sprague-Dawley rats aged 7-10 months are used in treatmentmode to simulate adult human females. The rats have been ovariectomized(OVX) 75-180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028 mpk SC, 2×/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15-31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-ike compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

[0422] In a typical assay, nine groups of seven rats each are studied.

[0423] On Days 19 and 29 (fifth and fifteenth days of treatment), asingle subcutaneous injection of calcein (8 mg/kg) is given to each rat.

[0424] Necropsy and Endpoints:

[0425] The rat is first weighed, then anesthetized in a CO₂ chamberuntil near death. Approximately 5 mL whole blood is obtained by cardiacpuncture. The rat is then examined for certain signs of death andcompleteness of OVX. First, the uterus is located, blunt dissected freein a highly stylized fashion, blotted dry for 3-5 seconds and thenweighed (UW). The uterus is placed in 10% neutral-buffered formalin.Next, the right leg is disarticulated at the hip. The femur and tibiaare separated at the knee, substantially defleshed, and then placed in70% ethanol.

[0426] A 1-cm segment of the central right femur, with the femoralproximal-distal midpoint ats center, is placed in a scintillation vialand dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10%dibutyl phthalate, that is allowed to polymerize over a 48-72 hr period.The bottle is cracked and the plastic block is trimmed into a shape thatconveniently fits the vice-like specimen holder of a Leica 1600 SawMicrotome, with the long axis of the bone prepared for cross-sectioning.Three cross-sections of 85 μm thickness are prepared and mounted onglass slides. One section from each rat that approximates the midpointof the bone is selected and blind-coded. The periosteal surface of eachsection is assessed for total periosteal surface, single fluorochromelabel, double fluorochrome label, and interlabel distance.

[0427] Primary data for this assay are the percentage of periostealsurface bearing double label and the mineral apposition rate (interlabeldistance(μm)/10 d), semi-independent markers of bone formation.Secondary data include uterus weight and histologic features. Tertiaryendpoints may include serum markers of bone formation and virilization.Data are analyzed by ANOVA plus Fisher PLSD post-hoc test to identifyintergroup differences. The extent to which test compounds increase boneformation endpoint are assessed.

[0428] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it is understood that the practice of the inventionencompasses all of the usual variations, adoptions, or modifications, asbeing within the scope of the following claims and their equivalents.

What is claimed is:
 1. A method for modulating a function mediated bythe androgen receptor in a tissue selective manner in a subject in needthereof comprising administering a therapeutically effective amount of acompound of structural formula

or a pharmaceutically acceptable salt thereof; wherein “a” represents asingle bond or a double bond; R¹ is selected from the group consistingof hydrogen, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, phenyl, and phenyl C₁₋₃ alkyl;in which alkyl, cycloalkyl, and phenyl are unsubstituted or substitutedwith one to three groups independently selected from halogen, hydroxy,amino, carboxy, and C₁₋₄ alkoxy; R² and R³ are each independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, halogen,halogen C₁₋₄ alkyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl,C₁₋₆ alkylcarbonyloxy, (C₁₋₆)₀₋₂ aminocarbonyloxy, in which alkyl,alkenyl, alkynyl, and cycloalkyl are unsubstituted or substituted withone to three substituents independently selected from halogen, hydroxy,carboxy, and C₁₋₄ alkoxy; or R² and R³ are taken together with thecarbon atom to which they are attached to form a carbonyl group, aC₁₋₆alkylidene group, or a spiro-C₃₋₆ cycloalkyl group, unsubstituted orsubstituted with C₁₋₄ alkyl; or R² and R⁷ are taken together with thecarbon atoms to which they are attached to form a fused cyclopropylring; R⁴ is hydrogen or C₁₋₄ alkyl; R⁵ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, and phenyl C₁₋₃ alkyl;R⁶ is aryl wherein the aryl group is selected from the group consistingof (1) phenyl, (2) naphthyl, (3) benzimidazolyl, (4) benzofuranyl, (5)benzothiophenyl, (6) benzoxazolyl, (7) benzothiazolyl, (8)benzodihydrofuranyl, (9) indolyl, (10) quinolyl, (11) isoquinolyl, (12)furanyl, (13) thienyl, (14) imidazolyl, (15) oxazolyl, (16) thiazolyl,(17) isoxazolyl, (18) isothiazolyl, (19) pyrazolyl, (20) pyrrolyl, (21)pyridyl, (22) pyrimidyl, (23) pyrazinyl, (24) thiadiazolyl, (25)oxadiazolyl, (26) triazolyl, and (27) tetrazolyl; wherein the aryl groupas defined above items (1) to (27) is unsubstituted or substituted withone to three substituents independently selected from halogen, C₁₋₈alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, phenyl, phenyl C₁₋₃alkyl, amino, amino C₁₋₆ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₆alkyl, C₁₋₆ alkylamino, di-(C₁₋₆ alkyl)amino, di-(C₁₋₆ alkyl)amino C₁₋₆alkyl, C₁₋₆ alkylamino C₁₋₆ alkyl, aminocarbonylamino, C₁₋₄ alkoxy, C₁₋₄alkoxy C₁₋₆ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylsulfonylamino, carboxy, carboxy C₁₋₆ alkyl,C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, C₁₋₅alkylcarbonyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and trifluoroethoxy; and R⁷ ishydrogen or C₁₋₄ alkyl.
 2. A method of activating the function of theandrogen receptor comprising administering to a subject in need thereofa therapeutically effective amount of a compound of structural formulaI:

or a pharmaceutically acceptable salt thereof; wherein “a” represents asingle bond or a double bond; R¹ is selected from the group consistingof hydrogen, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, phenyl, and phenyl C₁₋₃ alkyl;in which alkyl, cycloalkyl, and phenyl are unsubstituted or substitutedwith one to three groups independently selected from halogen, hydroxy,amino, carboxy, and C₁₋₄ alkoxy; R² and R³ are each independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, halogen,halogen C₁₋₄ alkyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl,C₁₋₆ alkylcarbonyloxy, (C₁₋₆)₀₋₂ aminocarbonyloxy, in which alkyl,alkenyl, alkynyl, and cycloalkyl are unsubstituted or substituted withone to three substituents independently selected from halogen, hydroxy,carboxy, and C₁₋₄ alkoxy; or R² and R³ are taken together with thecarbon atom to which they are attached to form a carbonyl group, a C₁₋₆alkylidene group, or a spiro-C₃₋₆ cycloalkyl group, unsubstituted orsubstituted with C₁₋₄ alkyl; or R² and R⁷ are taken together with thecarbon atoms to which they are attached to form a fused cyclopropylring; R⁴ is hydrogen or C₁₋₄ alkyl; R⁵ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, and phenyl C₁₋₃ alkyl;R⁶ is aryl wherein the aryl group is selected from the group consistingof (1) phenyl, (2) naphthyl, (3) benzimidazolyl, (4) benzofuranyl, (5)benzothiophenyl, (6) benzoxazolyl, (7) benzothiazolyl, (8)benzodihydrofuranyl, (9) indolyl, (10) quinolyl, (11) isoquinolyl, (12)furanyl, (13) thienyl, (14) imidazolyl, (15) oxazolyl, (16) thiazolyl,(17) isoxazolyl, (18) isothiazolyl, (19) pyrazolyl, (20) pyrrolyl, (21)pyridyl, (22) pyrimidyl, (23) pyrazinyl, (24) thiadiazolyl, (25)oxadiazolyl, (26) triazolyl, and (27) tetrazolyl; wherein the aryl groupas defined above items (1) to (27) is unsubstituted or substituted withone to three substituents independently selected from halogen, C₁₋₈alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, phenyl, phenyl C₁₋₃alkyl, amino, amino C₁₋₆ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₆alkyl, C₁₋₆ alkylamino, di-(C₁₋₆ alkyl)amino, di-(C₁₋₆ alkyl)amino C₁₋₆alkyl, C₁₋₆ alkylamnino C₁₋₆ alkyl, aminocarbonylamino, C₁₋₄ alkoxy,C₁₋₄ alkoxy C₁₋₆ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylsulfonylamino, carboxy, carboxy C₁₋₆ alkyl,C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, C₁₋₅alkylcarbonyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and trifluoroethoxy; and R⁷ ishydrogen or C₁₋₄ alkyl
 3. The method of claim 1 wherein said functionmediated by the androgen receptor function is blocked in the prostate ofa male subject or in the uterus of a female subject and activated inbone and/or muscle tissue.
 4. The method of claim 3 wherein “a”represents a double bond and R⁷ is hydrogen or methyl.
 5. The method ofclaim 4 wherein R¹ is hydrogen or C₁₋₃ alkyl.
 6. The method of claim 4wherein R⁴ is hydrogen.
 7. The method of claim 4 wherein R⁵ is hydrogenor methyl and R⁶ is selected from the group consisting of phenyl,naphthyl, and pyridyl, unsubstituted or substituted with one to threegroups independently selected from halogen, nitro, trifluoromethyl, C₁₋₄alkyl, C₁₋₄ alkoxy, and cyano.
 8. The method of claim 7 wherein R⁶ isphenyl, unsubstituted or substituted with one to three groupsindependently selected from halogen, nitro, trifluoromethyl, methyl,methoxy, and cyano.
 9. The method of claim 4 wherein R² and R³ are eachhydrogen or are taken together with the carbon to which they areattached to form a spirocyclopropyl group or a methylene group.
 10. Themethod of claim 3 wherein the compound is of structural formula II:

or a pharmaceutically acceptable salt thereof; wherein R² and R³ arehydrogen or R² and R³ are taken together with the carbon atom to whichthey are attached to form a methylene or a spirocyclopropyl group; R⁵ ishydrogen or methyl; R⁶ is phenyl, naphthyl, or pyridyl, unsubstituted orsubstituted with one to three groups independently selected fromhalogen, C₁₋₄ alkyl, amino, C₁₋₃ acylamino, C₁₋₄ alkylamino, di-(C₁₋₄alkyl)amino, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfonylamino, carboxy, C₁₋₅ alkoxycarbonyl, C₁₋₅ alkylcarbonyloxy,hydroxy, cyano, nitro, and trifluoromethyl; and R⁷ is hydrogen ormethyl.
 11. The method of claim 3 wherein the compound is selected fromthe group consisting of:(17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-3-oxo-N-phenylandrost-4-ene-17-carboxamide;(17β)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-methyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-ethyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxamide;(17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;and (1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;or a pharmaceutically acceptable salt thereof.
 12. A method ofpreventing or treating a condition in a male subject which is caused byandrogen deficiency or which can be ameliorated by androgen replacementwhich condition is selected from the group consisting of osteoporosis,osteopenia, glucocorticoid-induced osteoporosis, periodontal disease,HIV-wasting, cancer cachexia, aplastic and other anemias, and musculardystrophies, comprising administering to the male subject in need ofsuch prevention or treatment a prophylactically or therapeuticallyeffective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein “a” represents asingle bond or a double bond; R¹ is selected from the group consistingof hydrogen, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, phenyl, and phenyl C₁₋₃ alkyl;in which alkyl, cycloalkyl, and phenyl are unsubstituted or substitutedwith one to three groups independently selected from halogen, hydroxy,amino, carboxy, and C₁₋₄ alkoxy; R² and R³ are each independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, halogen,halogen C₁₋₄ alkyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl,C₁₋₆ alkylcarbonyloxy, (C₁₋₆)₀₋₂ aminocarbonyloxy, in which alkyl,alkenyl, alkynyl, and cycloalkyl are unsubstituted or substituted withone to three substituents independently selected from halogen, hydroxy,carboxy, and C₁₋₄ alkoxy; or R² and R³ are taken together with thecarbon atom to which they are attached to form a carbonyl group, a C₁₋₆alkylidene group, or a spiro-C₃₋₆ cycloalkyl group, unsubstituted orsubstituted with C₁₋₄ alkyl; or R² and R⁷ are taken together with thecarbon atoms to which they are attached to form a cyclopropyl group; R⁴is hydrogen or C₁₋₄ alkyl; R⁵ is selected from the group consisting ofhydrogen, C₁₋₄ akyl, C₂₋₄ alkenyl, and phenyl C₁₋₃ alkyl; R⁶ is arylwherein the aryl group is selected from the group consisting of (1)phenyl, (2) naphthyl, (3) benzimidazolyl, (4) benzofuranyl, (5)benzothiophenyl, (6) benzoxazolyl, (7) benzothiazolyl, (8)benzodihydrofuranyl, (9) indolyl, (10) quinolyl, (11) isoquinolyl, (12)furanyl, (13) thienyl, (14) imidazolyl, (15) oxazolyl, (16) thiazolyl,(17) isoxazolyl, (18) isothiazolyl, (19) pyrazolyl, (20) pyrrolyl, (21)pyridyl, (22) pyrimidyl, (23) pyrazinyl, (24) thiadiazolyl, (25)oxadiazolyl, (26) triazolyl, and (27) tetrazolyl; wherein the aryl groupas defined above items (1) to (27) is unsubstituted or substituted withone to three substituents independently selected from halogen, C₁₋₈alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, phenyl, phenyl C₁₋₃alkyl, amino, amino C₁₋₆ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₆alkyl, C₁₋₆ alkylamino, di-(C₁₋₆ alkyl)amino, di-(C₁₋₆ alkyl)amino C₁₋₆alkyl, C₁₋₆ alkylamino C₁₋₆ alkyl, aminocarbonylamino, C₁₋₄ alkoxy, C₁₋₄alkoxy C₁₋₆ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylsulfonylamino, carboxy, carboxy C₁₋₆ alkyl,C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, C₁₋₅alkylcarbonyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and trifluoroethoxy; and R⁷ ishydrogen or C₁₋₄ alkyl.
 13. The method of claim 12 wherein saidcondition is osteoporosis.
 14. The method of claim 12 wherein thecompound is of structural formula II:

or a pharmaceutically acceptable salt thereof; wherein R² and R³ arehydrogen or R² and R³ are taken together with the carbon atom to whichthey are attached to form a methylene or a spirocyclopropyl group; R⁵ ishydrogen or methyl; R⁶ is phenyl, naphthyl, or pyridyl, unsubstituted orsubstituted with one to three groups independently selected fromhalogen, C₁₋₄ alkyl, amino, C₁₋₃ acylamino, C₁₋₄ alkylamino, di-(C₁₋₄alkyl)amino, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfonylamino, carboxy, C₁₋₅ alkoxycarbonyl, C₁₋₅ alkylcarbonyloxy,hydroxy, cyano, nitro, and trifluoromethyl; and R⁷ is hydrogen ormethyl.
 15. The method of claim 12 wherein the compound is selected fromthe group consisting of:(17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-3-oxo-N-phenylandrost-4-ene-17-carboxamide;(17β)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-methyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-ethyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxamide;(17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;and (1aS,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;or a pharmaceutically acceptable salt thereof.
 16. A method ofpreventing or treating a condition in a female subject which is causedby androgen deficiency or which can be ameliorated by androgenreplacement which condition is selected from the group consisting ofosteoporosis, osteopenia, glucocorticoid-induced osteoporosis,periodontal disease, HIV-wasting, cancer cachexia, aplastic and otheranemias, muscular dystrophies, premature ovarian failure, and autoimmunedisease, comprising administering to the female subject in need of suchprevention or treatment a prophylactically or therapeutically effectiveamount of a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein “a” represents asingle bond or a double bond; R¹ is selected from the group consistingof hydrogen, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, phenyl, and phenyl C₁₋₃ alkyl;in which alkyl, cycloalkyl, and phenyl are unsubstituted or substitutedwith one to three groups independently selected from halogen, hydroxy,amino, carboxy, and C₁₋₄ alkoxy; R² and R³ are each independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, halogen,halogen C₁₋₄ alkyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl,C₁₋₆ alkylcarbonyloxy, (C₁₋₆)₀₋₂aminocarbonyloxy, in which alkyl,alkenyl, alkynyl, and cycloalkyl are unsubstituted or substituted withone to three substituents independently selected from halogen, hydroxy,carboxy, and C₁₋₄ alkoxy; or R² and R³ are taken together with thecarbon atom to which they are attached to form a carbonyl group, a C₁₋₆alkylidene group, or a spiro-C₃₋₆ cycloalkyl group, unsubstituted orsubstituted with C₁₋₄ alkyl; or R² and R⁷ are taken together with thecarbon atoms to which they are attached to form a cyclopropyl group; R⁴is hydrogen or C₁₋₄ alkyl; R⁵ is selected from the group consisting ofhydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, and phenyl C₁₋₃ alkyl; R⁶ is arylwherein the aryl group is selected from the group consisting of (1)phenyl, (2) naphthyl, (3) benzimidazolyl, (4) benzofuranyl, (5)benzothiophenyl, (6) benzoxazolyl, (7) benzothiazolyl, (8)benzodihydrofuranyl, (9) indolyl, (10) quinolyl, (11) isoquinolyl, (12)furanyl, (13) thienyl, (14) imidazolyl, (15) oxazolyl, (16) thiazolyl,(17) isoxazolyl, (18) isothiazolyl, (19) pyrazolyl, (20) pyrrolyl, (21)pyridyl, (22) pyrimidyl, (23) pyrazinyl, (24) thiadiazolyl, (25)oxadiazolyl, (26) triazolyl, and (27) tetrazolyl; wherein the aryl groupas defined above items (1) to (27) is unsubstituted or substituted withone to three substituents independently selected from halogen, C₁₋₈alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, phenyl, phenyl C₁₋₃alkyl, amino, amino C₁₋₆ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₆alkyl, C₁₋₆ alkylamino, di-(C₁₋₆ alkyl)amino, di-(C₁₋₆ alkyl)amino C₁₋₆alkyl, C₁₋₆ alkylamino C₁₋₆ alkyl, aminocarbonylamino, C₁₋₄ alkoxy, C₁₋₄alkoxy C₁₋₆ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylsulfonylamino, carboxy, carboxy C₁₋₆ alkyl,C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, C₁₋₅alkylcarbonyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and trifluoroethoxy; and R⁷ ishydrogen or C₁₋₄ alkyl.
 17. The method of claim 16 wherein saidcondition is osteoporosis.
 18. The method of claim 16 wherein thecompound is of structural fonnula II:

or a pharmaceutically acceptable salt thereof; wherein R² and R³ arehydrogen or R² and R³ are taken together with the carbon atom to whichthey are attached to form a methylene or a spirocyclopropyl group; R⁵ ishydrogen or methyl; R⁶ is phenyl, naphthyl, or pyridyl, unsubstituted orsubstituted with one to three groups independently selected fromhalogen, C₁₋₄ alkyl, amino, C₁₋₃ acylamino, C₁₋₄ alkylamino, di-(C₁₋₄alkyl)amino, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfonylamino, carboxy, C₁₋₅ alkoxycarbonyl, C₁₋₅ alkylcarbonyloxy,hydroxy, cyano, nitro, and trifluoromethyl; and R⁷ is hydrogen ormethyl.
 19. The method of claim 16 wherein the compound is selected fromthe group consisting of:(17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-3-oxo-N-phenylandrost-4-ene-17-carboxamide;(17β)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-iodophenyl)-3-oxoandrostene-17-carboxamide;(17β)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-methyl-3-oxo4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-ethyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxamide;(17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;and (1aS,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;or a pharmaceutically acceptable salt thereof.
 20. The method of claim13 which further comprises the administration of a bone-strengtheningagent selected from the group consisting of: (a) an estrogen or anestrogen derivative, alone or in combination with a progestin orprogestin derivative, (b) a bisphosphonate, (c) an antiestrogen or aselective estrogen receptor modulator, (d) an αvβ3 integrin receptorantagonist, (e) a cathepsin K inhibitor, (f) an HMG-CoA reductaseinhibitor, (g) an osteoclast vacuolar ATPase inhibitor, (h) anantagonist of VEGF binding to osteoclast receptors, (i) an activator ofperoxisome proliferator-activated receptor γ, (j) calcitonin, (k) acalcium receptor antagonist, (l) parathyroid hormone or analog thereof,(m) a growth hormone secretagogue, (n) human growth hormone, (o)insulin-like growth factor, (p) a P-38 protein kinase inhibitor, (q)bone morphogenetic protein, (r) an inhibitor of BMP antagonism, (s) aprostaglandin derivative, (t) vitamin D or vitamin D derivative, (u)vitamin K or vitamin K derivative, (v) ipriflavone, (w) fluoride salts,(x) dietary calcium supplement, and (y) osteoprotegerin.
 21. The methodof claim 20 wherein: (a) the estrogen or estrogen derivative, alone orin combination with a progestin or progestin derivative, is selectedfrom conjugated estrogen, equine estrogen, 17β-estradiol, estrone,17β-ethynyl estradiol, alone or in combination with an agent selectedfrom norethindrone and medroxyprogesterone acetate; (b) thebisphosphonate is selected from: (1)(4-amino-1-hydroxybutylidene)-bisphosphonate; (2)[(cycloheptylamino)-methylene]-bisphosphonate; (3)(dichloromethylene)-bisphosphonate; (4)[1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bisphosphonate; (5)(1-hydroxyethylidene)-bisphosphonate; (6)[1-hydroxy-3-(methylpentylamino)propylidene]-bisphosphonate; (7)(6-amino-1-hydroxyhexylidene)-bisphosphonate; (8)[3-(dimethylamino)-1-hydroxypropylidene]-bisphosphonate; (9)(3-amino-1-hydroxypropylidene)-bisphosphonate; (10)[2-(2-pyridinyl)ethylidene]-bisphosphonate; (11)[1-hydroxy-2-(3-pyridinyl)-ethylidene]-bisphosphonate; (12){[(4-chlorophenyl)thio]methylene}-bisphosphonate; (13)[1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bisphosphonate; and (14)[1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bisphosphonate; (c)the antiestrogen or selective estrogen receptor modulator is selectedfrom the group consisting of raloxifene, clomiphene, zuclomiphene,enclomiphene, nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25,U-11,555A, U-100A, tamoxifen, lasofoxifene, toremifene, azorxifene,EM-800, EM-652, TSE 424, droloxifene, idoxifene, and levormeloxifene;(d) the HMG-CoA reductase inhibitor is selected from lovastatin,simvastatin, dihydroxy-open acid simvastatin, pravastatin, fluvastatin,atorvastatin, cerivastatin, rosuvastatin, pitavastatin, and nisvastatin;(e) calcitonin is salmon calcitonin administered as a nasal spray; (f)bone morphogenetic protein is selected from BMP 2, BMP 3, BMP 5, BMP 6,BMP 7, TGF beta, and GDF5; (g) insulin-like growth factor is selectedfrom IGF I and IGF II alone or in combination with IGF binding protein3; (h) the prostaglandin derivative is selected from agonists ofprostaglandin receptors EP1, EP2, EP4, FP, and IP; (i) the fibroblastgrowth factor is selected from aFGF and bFGF; (j) parathyroid hormone(PTH) or PTH analog is selected from PTH subcutaneous injection, humanPTH (1-84), human PTH (1-34), and other partial sequences, native orwith substitutions; (k) vitamin D or vitamin D derivative is selectedfrom natural vitamin D, 25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3,1α-OH-vitamin D3, 1α-OH-vitamin D2, dihydrotachysterol,26,27-F6-1α,25(OH)₂ vitamin D3, 19-nor-1α,25(OH)₂ vitamin D3,22-oxacalcitriol, calcipotriol, 1α,25(OH)₂-16-ene-23-yne-vitamin D3 (Ro23-7553), EB1089, 20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71,1α,24(S)-(OH)₂ vitamin D3, and 1α,24(R)-(OH)₂ vitamin D3; (l) thedietary calcium supplement is selected from calcium carbonate, calciumcitrate, and natural calcium salts; and (m) the fluoride salts areselected from sodium fluoride and monosodium fluorophosphate (MFP); andpharmaceutically acceptable salts thereof.
 22. The method of claim 13which further comprises the administration of alendronate monosodiumtrihydrate.
 23. The method of claim 17 which further comprises theadministration of a bone-strengthening agent selected from the groupconsisting of: (a) an estrogen or an estrogen derivative, alone or incombination with a progestin or progestin derivative, (b) abisphosphonate, (c) an antiestrogen or a selective estrogen receptormodulator, (d) an αvβ3 integrin receptor antagonist, (e) a cathepsin Kinhibitor, (f) an HMG-CoA reductase inhibitor, (g) an osteoclastvacuolar ATPase inhibitor, (h) an antagonist of VEGF binding toosteoclast receptors, (i) an activator of peroxisomeproliferator-activated receptor γ, (j) calcitonin, (k) a calciumreceptor antagonist, (l) parathyroid hormone or analog thereof, (m) agrowth hormone secretagogue, (n) human growth hormone, (o) insulin-likegrowth factor, (p) a P-38 protein kinase inhibitor, (q) bonemorphogenetic protein, (r) an inhibitor of BMP antagonism, (s) aprostaglandin derivative, (t) vitamin D or vitamin D derivative, (u)vitamin K or vitamin K derivative, (v) ipriflavone, (w) fluoride salts,(x) dietary calcium supplement, and (y) osteoprotegerin.
 24. The methodof claim 23 wherein: (a) the estrogen or estrogen derivative, alone orin combination with a progestin or progestin derivative, is selectedfrom conjugated estrogen, equine estrogen, 17β-estradiol, estrone,17β-ethynyl estradiol, alone or in combination with an agent selectedfrom norethindrone and medroxyprogesterone acetate; (b) thebisphosphonate is selected from: (1)(4-amino-1-hydroxybutylidene)-bisphosphonate; (2)[(cycloheptylamino)-methylene]-bisphosphonate; (3)(dichloromethylene)-bisphosphonate; (4)[1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bisphosphonate; (5)(1-hydroxyethylidene)-bisphosphonate; (6)[1-hydroxy-3-(methylpentylamino)propylidene]-bisphosphonate; (7)(6-amino-1-hydroxyhexylidene)-bisphosphonate; (8)[3-(dimethylamino)-1-hydroxypropylidene]-bisphosphonate; (9)(3-amino-1-hydroxypropylidene)-bisphosphonate; (10)[2-(2-pyridinyl)ethylidene]-bisphosphonate; (11)[1-hydroxy-2-(3-pyridinyl)-ethylidene]-bisphosphonate; (12){[(4-chlorophenyl)thio]methylene}-bisphosphonate; (13)[1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bisphosphonate; and (14)[1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bisphosphonate; (c)the antiestrogen or selective estrogen receptor modulator is selectedfrom the group consisting of raloxifene, clomiphene, zuclomiphene,enclomiphene, nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25,U-11,555A, U-100A, tamoxifen, lasofoxifene, toremifene, azorxifene,EM-800, EM-652, TSE 424, droloxifene, idoxifene, and levormeloxifene;(d) the HMG-CoA reductase inhibitor is selected from lovastatin,simvastatin, dihydroxy-open acid simvastatin, pravastatin, fluvastatin,atorvastatin, cerivastatin, rosuvastatin, pitavastatin, and nisvastatin;(e) calcitonin is salmon calcitonin administered as a nasal spray; (f)bone morphogenetic protein is selected from BMP 2, BMP 3, BMP 5, BMP 6,BMP 7, TGF beta, and GDF5; (g) insulin-like growth factor is selectedfrom IGF I and IGF II alone or in combination with IGF binding protein3; (h) the prostaglandin derivative is selected from agonists ofprostaglandin receptors EP1, EP2, EP4, FP, and IP; (i) the fibroblastgrowth factor is selected from aFGF and bFGF; (j) parathyroid hormone(PTH) or PTH analog is selected from PTH subcutaneous injection, humanPTH (1-84), human PTH (1-34), and other partial sequences, native orwith substitutions; (k) vitamin D or vitamin D derivative is selectedfrom natural vitamin D, 25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3,1α-OH-vitamin D3, 1α-OH-vitamin D2, dihydrotachysterol,26,27-F6-1α,25(OH)₂ vitamin D3, 19-nor-1α,25(OH)₂ vitamin D3,22-oxacalcitriol, calcipotriol, 1α,25(OH)₂-16-ene-23-yne-vitamin D3 (Ro23-7553), EB1089, 20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71,1α,24(S)-(OH)₂ vitamin D3, and 1α,24(R)-(OH)₂ vitamin D3; (l) thedietary calcium supplement is selected from calcium carbonate, calciumcitrate, and natural calcium salts; and (m) the fluoride salts areselected from sodium fluoride and monosodium fluorophosphate (MFP); andpharmaceutically acceptable salts thereof.
 25. The method of claim 17which further comprises the administration of alendronate monosodiumtrihydrate.
 26. A composition comprising a compound according to claim1, or a pharmaceutically acceptable salt thereof, and abone-strengthening agent selected from the group consisting of: (a) anestrogen or an estrogen derivative, alone or in combination with aprogestin or progestin derivative, (b) a bisphosphonate, (c) anantiestrogen or a selective estrogen receptor modulator, (d) an αvβ3integrin receptor antagonist, (e) a cathepsin K inhibitor, (f) anHMG-CoA reductase inhibitor, (g) an osteoclast vacuolar ATPaseinhibitor, (h) an antagonist of VEGF binding to osteoclast receptors,(i) an activator of peroxisome proliferator-activated receptor γ, (j)calcitonin, (k) a calcium receptor antagonist, (l) parathyroid hormoneor analog thereof, (m) a growth hormone secretagogue, (n) human growthhormone, (o) insulin-like growth factor, (p) a P-38 protein kinaseinhibitor, (q) bone morphogenetic protein, (r) an inhibitor of BMPantagonism, (s) a prostaglandin derivative, (t) vitarmin D or vitamin Dderivative, (u) vitamin K or vitamin K derivative, (v) ipriflavone, (w)fluoride salts, (x) dietary calcium supplement, and (y) osteoprotegerin.27. A compound selected from the group consisting of:(17β)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxatide;(17β)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-carboxamide;(17β)-N-methyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-etyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-carboxamide;(17β)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6-methylene-3-oxo-N-(4-trifluorornethylphenyl)-androst-4-ene-17-carboxamide;(17β)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxamide;(17β)-6α-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6β-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(17β)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxamide;(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;and (1aS,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;or a pharmaceutically acceptable salt thereof.
 28. A compositioncomprising a compound according to claim 27 and a pharmaceuticallyacceptable carrier.
 29. The use of a compound of structural formula Ifor the preparation of a medicament useful for modulating the androgenreceptor in a tissue selective manner in a patient in need of suchmodulation.
 30. The use of a compound according to claim 1, or apharmaceutically acceptable salt thereof, for the preparation of amedicament useful for activating the function of the androgen receptorin a patient in need thereof.
 31. The use of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament useful for treating a condition in a patientin need of such treatment which is caused by androgen deficiency orwhich can be ameliorated by androgen administration selected from thegroup consisting of osteoporosis, periodontal disease, bone fracture,bone damage following bone reconstructive surgery, sarcopenia, frailty,aging skin, male hypogonadism, female sexual dysfunction,post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, aplastic anemia and otherhematopoietic disorders, pancreatic cancer, renal cancer, prostatecancer, arthritis and joint repair.
 32. The method of claim 13 whereinthe bone-strengthening agent is selected from the group consisting of:(a) an estrogen or an estrogen derivative, alone or in combination witha progestin or progestin derivative, (b) a bisphosphonate, (c) anantiestrogen or a selective estrogen receptor modulator, (d) an αvβ3integrin receptor antagonist, (e) a cathepsin K inhibitor, (f) anosteoclast vacuolar ATPase inhibitor, (g) calcitonin, and (h)osteoprotegerin.
 33. The method of claim 17 wherein thebone-strengthening agent is selected from the group consisting of: (a)an estrogen or an estrogen derivative, alone or in combination withprogestin or progestin derivative, (b) a bisphosphonate, (c) anantiestrogen or a selective estrogen receptor modulator, (d) an αvβ3integrin receptor antagonist, (e) a cathepsin K inhibitor, (f) anosteoclast vacuolar ATPase inhibitor, (g) calcitonin, and (h)osteoprotegerin.